BACKGROUND & AIMS: No one knows exactly what proportion of gallstones cause clinical events among subjects unaware of their gallstone status. We investigated the long-term occurrence of clinical events of gallstones and associations between ultrasound observations and clinical events. METHODS: We analyzed data from 3 randomly selected groups in the general population of urban Copenhagen (age, 30-70 y) participating in an international study of cardiovascular risk factors (the Multinational mONItoring of trends and determinants in CArdiovascular disease study). In this study, participants (n = 6037) were examined from 1982 through 1994, and underwent abdominal ultrasound examinations to detect gallstones. Our study population comprised 664 subjects with gallstones; subjects were not informed of their gallstone status. Participants were followed up for clinical events through central registers until December 31, 2011. Independent variables included ultrasound characteristics, age, sex, comorbidity, and female-associated factors, which were analyzed using Cox regression. RESULTS: Study participants were followed up for a median of 17.4 years (range, 0.1-29.1 y); 99.7% of participants completed the study. A total of 19.6% participants developed events (8.0% complicated and 11.6% uncomplicated). Ten percent had awareness of their gallstones; awareness was associated with uncomplicated and complicated events. Stones larger than 10 mm were associated with all events (hazard ratio [HR], 2.31; 95% confidence interval [CI], 1.45-3.69), acute cholecystitis (HR, 9.49; 95% CI, 2.05-43.92), and uncomplicated events (HR, 2.55; 95% CI, 1.38-4.71), including cholecystectomy (HR, 2.69; 95% CI, 1.29-5.60). Multiple stones were associated with all events (HR, 1.68; 95% CI, 1.00-2.81), complicated events (HR, 2.52; 95% CI, 1.05-6.04), and common bile duct stones (HR, 11.83; 95% CI, 1.54-91). There was an association between gallstones more than 5 years old and acute cholecystitis. Female sex was associated with all and uncomplicated events. We found a negative association between participant age and all events, uncomplicated events, and acute cholecystitis. Comorbidities and female-associated factors (intake of birth control pills or estrogens and number of births) were not associated with events. Compared with men with a single stone of 10 mm or smaller (reference), women with multiple stones greater than 10 mm had the highest risk for events (HR, 11.05; 95% CI, 3.76-32.44; unadjusted absolute risk, 0.0235 events/person-years). CONCLUSIONS: Fewer than 20% of subjects with gallstones develop clinical events. Larger, multiple, and older gallstones are associated with events. Further studies are needed to confirm the prediction rules.