The Centers for Disease Control and Prevention (CDC) has estimated that Shiga toxin-producing Escherichia coli O157 (0157 STEC) infections cause 73,000 illnesses annually in the United States, resulting in more than 2,000 hospitalizations and 60 deaths. In this study, the economic cost of illness due to O157 STEC infections transmitted by food or other means was estimated based on the CDC estimate of annual cases and newly available data from the Foodborne Diseases Active Surveillance Network (FoodNet) of the CDC Emerging Infections Program. The annual cost of illness due to O157 STEC was $405 million (in 2003 dollars), including $370 million for premature deaths, $30 million for medical care, and $5 million in lost productivity. The average cost per case varied greatly by severity of illness, ranging from $26 for an individual who did not obtain medical care to $6.2 million for a patient who died from hemolytic uremic syndrome. The high cost of illness due to O157 STEC infections suggests that additional efforts to control this pathogen might be warranted.