American Express is cutting about 4,000 jobs - approximately 6% of its global workforce - as part of a plan to save $US800 million this year.
The move is in addition to the 7,000 job cuts it announced in October 2008, the BBC reports.
The firm has large numbers of small business customers - and Amex said that these businesses were more likely to miss repayments than individuals.
The credit card firm is also suffering from a fall in consumer spending - as house prices continue to struggle.
In April, American Express reported that profit in the first three months of 2009 had fallen by 63%.
As well as the job cuts, the company has also stopped management-level salary rises and has frozen recruitment.
In the United States, legislation is planned that would stop credit card issuers from imposing arbitrary interest rate increases and penalties.
In April, US President Barack Obama told the credit card industry in America to scrap unfair interest rate rises and to be more transparent and accountable.