Background: Monounsaturated and polyunsaturated fats act as inhibitors of cholesterol cholelithiasis in animal experiments. Objective: To examine the association between long term intake of cis unsaturated fats and the incidence of gallstone disease in humans. Design: Prospective population based cohort study. Setting: The Health Professional Follow up Study. Participants: 45 756 men, age 40 to 75 years in 1986, who were free of gallstone disease. Measurements: Consumption of cis unsaturated fats was assessed starting in 1986 as part of the 131 item semi quantitative food frequency questionnaires. Questionnaires were mailed to participants every 2 years. The main outcome measure was self reported newly diagnosed symptomatic gallstone disease. Results: During 14 years of follow up, 2323 new cases of gallstone disease were documented. After adjustment for age and other potential risk factors, the relative risk for gallstone disease among men in the highest quintile of dietary intake of cis unsaturated fats compared with men in the lowest quintile was 0.82 (95%CI, 0.69 to 0.96; P for trend = 0.006). The relative risk among men in the highest quintile of polyunsaturated fat consumption compared with men in the lowest quintile was 0.84 (CI, 0.73 to 0.96; P for trend = 0.01), and the relative risk among men in the highest quintile of monounsaturated fat consumption compared with men in the lowest quintile was 0.83 (CI, 0.70 to 1.00; P for trend = 0.01). Limitations: Outcomes were restricted to men with cholecystectomy or diagnostically confirmed but unremoved symptomatic gallstones. Conclusions: A high intake of polyunsaturated and monounsaturated fats in the context of an energy balanced diet is associated with a reduced risk for gallstone disease in men. Background: Monounsaturated and polyunsaturated fats act as inhibitors of cholesterol cholelithiasis in animal experiments. Objective: To examine the association between long term intake of cis unsaturated fats and the incidence of gallstone disease in humans. Design: Prospective population based cohort study. Participants: 45 756 men, age 40 to 75 years in 1986, who were free of gallstone disease. Measurements: Consumption of cis unsaturated fats was assessed starting in 1986 as part of the 131 item semi quantitative food frequency questionnaires The main outcome measure was self reported newly diagnosed symptomatic gallstone disease. Results: During 14 years of follow up, 2323 new cases of gallstone disease were documented. After adjustment for age and other potential risk factors , the relative risk for gallstone disease among men in the highest quintile of dietary intake of c is unsaturated fats compared with men in the lowest quintile was 0.82 (95% CI, 0.69 to 0.96; P for trend = 0.006). The relative risk among men in the highest quintile of polyunsaturated fat consumption compared with men in the lowest quintile was 0.84 (CI, 0.73 to 0.96; P for trend = 0.01), and the relative risk among men in the highest quintile of monounsaturated fat consumption compared with men in the lowest quintile was 0.83 (CI, 0.70 to 1.00; P for trend = 0.01) . Limitations: Outcomes were restricted to men with cholecystectomy or diagnostically confirmed but unremoved symptomatic gallstones. Conclusions: A high intake of polyunsaturated and monounsaturated fats in the context of an energy balanced diet is associated with a reduced risk for gallstone disease in men.