Context: Coffee has several metabolic effects that could reduce the risk of gallstone formation. Objective: To examine the association between coffee consumption and the risk of symptomatic gallstone disease in men. Design and Setting: The Health Professionals Follow-up Study, a prospective cohort study, in which the consumption of coffee and other caffeinated drinks was assessed starting in 1986 as part of the 131-item food frequency questionnaire given to US male health professionals with follow-up through 1996. Participants: A total of 46 008 men, aged 40 to 75 years in 1986, without history of gallstone disease. Main Outcome Measures: Newly symptomatic gallstone disease (diagnosed by ultrasonography or x-ray) or a cholecystectomy. Results: During 404166 person-years of follow-up, 1081 subjects reported symptomatic gallstone disease, of whom 885 required cholecystectomy. After adjusting for other known or suspected risk factors, compared with men who did not consume regular coffee in 1986 and 1990, the adjusted relative risk (RR) for those who consistently drank 2 to 3 cups of regular coffee per day was 0.60 (95% confidence interval [CI], 0.42-0.86) and for those who drank 4 or more cups per day the RR was 0.55 (95% CI, 0.33- 0.92). All coffee brewing methods showed a decreased risk. The risk of symptomatic gallstone disease also declined with increasing caffeine intake (P for trend = .005). After controlling for known or suspected risk factors, the RR for men in the highest category of caffeine intake (>800 mg/d) compared with men in the lowest category (≤25 mg/d) was 0.55 (95% CI, 0.35- 0.87). In contrast, decaffeinated coffee was snot associated with a decreased risk. Conclusions: In this cohort of US men, coffee consumption may have helped to prevent symptomatic gallstone disease.