Wachovia has become the latest in a succession of leading US banks to part company with its chief executive.
The company said that Ken Thompson would be retiring at the request of its board of directors.
Lanty Smith, who replaced him as chairman in April, has been named as interim chief executive.
Wachovia, the fourth-largest US bank, lost $708m (£361m) in the first three months of 2008, had to raise an extra $8bn of capital and cut its dividend.
"A series of previously disclosed disappointments and setbacks cumulatively have negatively impacted the company and its performance," Lanty Smith said in a statement.
"The board believes new leadership will help to revitalise and re-energize Wachovia, and enable it to realise its potential."
Mr Thompson's departure follows those of the chief executives of Citigroup and Merrill Lynch.
He has been criticised for his $24.2bn acquisition of Golden West Financial Corp, a specialist mortgage lender. in October 2006.
Rising default rates from Golden West's loans have been a big contributor to Wachovia's problems.
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