OBJECTIVE: To examine associations between thigh circumference and incident cardiovascular disease and coronary heart disease and total mortality. DESIGN: Prospective observational cohort study with Cox proportional hazards model and restricted cubic splines. SETTING: Random subset of adults in Denmark. PARTICIPANTS: 1436 men and 1380 women participating in the Danish MONICA project, examined in 1987-8 for height, weight, and thigh, hip, and waist circumference, and body composition by impedance. MAIN OUTCOME MEASURES: 10 year incidence of cardiovascular and coronary heart disease and 12.5 years of follow-up for total death. RESULTS: A small thigh circumference was associated with an increased risk of cardiovascular and coronary heart diseases and total mortality in both men and women. A threshold effect for thigh circumference was evident, with greatly increased risk of premature death below around 60 cm. Above the threshold there seemed to be no additional benefit of having larger thighs in either sex. These findings were independent of abdominal and general obesity, lifestyle, and cardiovascular risk factors such as blood pressure and lipid concentration. CONCLUSION: A low thigh circumference seems to be associated with an increased risk of developing heart disease or premature death. The adverse effects of small thighs might be related to too little muscle mass in the region. The measure of thigh circumference might be a relevant anthropometric measure to help general practitioners in early identification of individuals at an increased risk of premature morbidity and mortality.