According to epidemiological studies, gallstone disease is a very common disease in Mexican-Americans and Mexicans. However, the major risk factors for cholelithiasis in Mexicans have not been identified. We designed a case-control study in a group of Mexican subjects with and without gallstone disease confirmed by ultrasound. These subjects were prospectively studied over a three-year period. Clinical and epidemiological data were collected by means of a questionnaire. A total of 1500 subjects were included in this study: 1000 with and 500 without gallstone disease. The major risk factor in both men and women was body mass index [odds ratio (OR) 1.64 and 1.96, respectively; P < 0.008 and 0.001]. In addition, parity was an important factor in women (OR 2.17, P < 0.001), whereas age was associated with gallstone disease in men (OR 1.43, P < 0.001). We found that body mass index, parity, and age were the principal risk factors for gallstone disease in this group of Mexican subjects. These results are similar to those found in Mexican-American populations.