"There was a demand made by the board of directors and he resigned," his wife Sabina Ratti, was quoted as saying by Italian news agencies Ansa and Radiocor.
A bank spokesman said a statement would be issued later and did not give details.
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The bank held an emergency board meeting on Tuesday to discuss the row, which has pitted some of the bank's Italian and German shareholders against Profumo.
Profumo has been chief executive since 1997 and has overseen a major international expansion drive by the bank, particularly into central and eastern Europe. In 2005, the bank merged with German lender HVB.
He is also president of the European Banking Federation in Brussels.
A report by Dow Jones Newswires quoting an anonymous source earlier said that Profumo had resigned and that bank chairman Dieter Rampl would now take up most of his duties as shareholders try to find a new CEO.
The stakes in Unicredit held by the Libyan central bank and the Libyan Investment Authority have risen this year to a total of more than 7.5 per cent, making the Libyan state the largest single shareholder in the bank.
This has stoked anger among some other shareholders, who have accused Profumo of failing to inform them of these developments, the reports said.
Tensions were already simmering because of the bank's poor earnings, with net profit last year plunging 57.6 per cent to 1.702 billion euros ($A2.35 billion)
Shares in Unicredit were down 2.11 per cent on the Milan stock exchange at the close of trading, while the benchmark FTSE Mib index slipped 0.06 per cent.
Unicredit is one of the biggest banks in Europe. It has a market capitalisation of $US37.3 billion euros ($A39.43 billion) and around 162,000 employees.
Shareholders include several Italian bank foundations, German insurance giant Allianz and the Aabar Fund from Abu Dhabi.
