Sir Paul said his integrity was intact, but referred to the PM's former aide Andy Coulson. The ex-NoW editor and Mr Wallis have been questioned by police.
The PM said the Met Police's inquiry must go "wherever the evidence leads".
He made the comments at a press conference in South Africa, where he is currently on a trade visit aimed at boosting dealings with emerging African economies.
The prime minister has cut the trip from five days to two amid the continuing phone-hacking scandal.
Mr Cameron thanked Sir Paul for "the great work he has done in policing over many, many years".
And, referring to the continued fall-out from the phone-hacking inquiry, he said: "The Metropolitan Police Service inquiry must go wherever the evidence leads. They should investigate without fear or favour.
"I have said that repeatedly and it's absolutely vital they feel that."
During the press conference, Mr Cameron was asked about the difference between him employing former NoW editor Mr Coulson as his director of communications and the Met's employment of Mr Wallis as a public relations adviser.
The prime minister said: "I don't believe the two situations are the same in any shape or form.
"In terms of Andy Coulson, no-one has argued that the work he did in government in any way was inappropriate or bad. He worked well in government and then left government.
"There is a contrast with the situation at the Metropolitan Police where, clearly, the issues have been around whether or not the investigation is being pursued properly."
Potential suspect
At the weekend, Sir Paul was criticised for having hired former News of the World executive Neil Wallis as an adviser.
Mr Wallis was arrested and released on bail on Thursday on suspicion of conspiring to intercept communications.
In his resignation statement, the outgoing Met Police chief suggested that Mr Cameron's relationship with Mr Coulson, his former Downing Street director of communications, had caused him difficulties.

In his statement, Sir Paul said: "Unlike Mr Coulson, Mr Wallis had not resigned from News of the World or, to the best of my knowledge, been in any way associated with the original phone-hacking investigation."
He went on: "Once Mr Wallis's name did become associated with Operation Weeting, I did not want to compromise the prime minister in any way by revealing or discussing a potential suspect who clearly had a close relationship with Mr Coulson.
"I am aware of the many political exchanges in relation to Mr Coulson's previous employment - I believe it would have been extraordinarily clumsy of me to have exposed the prime minister, or by association the home secretary, to any accusation, however unfair, as a consequence of them being in possession of operational information in this regard. Similarly, the mayor.
"Because of the individuals involved, their positions and relationships, these were I believe unique circumstances."
Labour shadow home secretary Yvette Cooper said that if Sir Paul felt that the "compromised relationship" between the prime minister and Mr Coulson "prevented him from telling the home secretary what was happening" and discussing operational matters with the home secretary, it meant the Met commissioner had been put in "an extremely difficult situation".
'Problem of perceptions' Home Secretary Theresa May told BBC Radio 4's Today programme that both she and the prime minister had been clear that "the Metropolitan Police must investigate all allegations and investigate all evidence and take it as far as it goes".
"If the Metropolitan Police found, at any stage, that they have a potential conflict of interest, I think it's right for them to be transparent about that," she said.

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The Home Secretary Theresa May says: "I didn't play a part in his resignation, it is entorely Sir Paul's decison."
He said it was Mr Cameron's links to Mr Coulson which still threatened to cause the most damage to the prime minister over the hacking scandal.
Our correspondent said it was clear that there was immense political pressure on Sir Paul after the Mayor of London, Boris Johnson, told him that his confidence in him had been severely shaken.
Mr Johnson told the BBC he was angry that he had not been told that Mr Wallis had later worked for Scotland Yard.
He said: "The whole thing added up to a problem - a problem of perceptions that was just going to go on and on. And he [Sir Paul] felt, as a guy who really loves ... takes huge pride in his job, who has done a great deal of good, that he didn't want to be endlessly sitting there answering inquiries, answering questions about phone hacking."
The mayor also referred to questions about the ongoing role of Metropolitan Police Assistant Commissioner John Yates, which he suggested would be addressed at a meeting later of the Metropolitan Police Authority (MPA), which scrutinises the police service's work.
The home secretary is set to make a statement to the House of Commons later over the links between the Met and News International.
And Labour leader Ed Miliband is to blame the scandal on a culture of "irresponsibility" that also led to the banking crisis and MPs' abuse of their expenses.
In a speech later, he will say that all three episodes were caused by some of the most powerful people in society thinking they were "untouchable" and could act as they pleased.
Rebekah Brooks, the former News International chief executive who had been editor of the News of the World when some alleged hacking took place, was arrested and released on bail on Sunday as part of the investigation.
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