WASHINGTON—Some of the most heavily traded U.S. stocks might also be among the most expensive to trade, costing investors as much as $2.5 billion a year, according to a New York trading and research firm.

Stocks such as Bank of America Corp., Microsoft Corp., Cisco Systems Inc., and Ford Motor Co. are so popular with high-frequency trading firms that long-term investors often have trouble quickly buying and selling the stocks, according to a report by Pragma Securities LLC.

Investors...