At the present time, no study has yet clearly established whether tobacco smoking is a risk factor of lower limb venous insufficiency. This case-control study was initiated in France to determine the possible etiologic relation between tobacco smoking and lower limb venous insufficiency. A total of 1,806 cases suffering from lower limb venous insufficiency, recruited by 460 general practitioners between April 1997 and April 1998, were matched by age and gender to 1,806 controls. Data were collected on the physical examination, medical reason for consulting, current treatments, smoking habits, and known risk factors of lower limb venous insufficiency. Conditional logistic regression for the statistical analyses was performed. Known risk factors of lower limb venous insufficiency were confirmed in the overall model: family history of venous insufficiency (odds ratio (OR) = 7.7), frequent (OR = 1.4) or regular (OR = 2.7) prolonged standing at work, heat exposure (OR = 2.0), low physical activity (OR = 1.6), and (for women) more than four pregnancies (OR = 3.4). Multivariate analysis adjusted for other risk factors showed that lower limb venous insufficiency is significantly associated with tobacco smoking (OR = 1.7 for 10-19 cigarettes/day and OR = 2.4 for 20 cigarettes/day or more; p < 0.001). These results suggest that smoking is significantly associated with lower limb venous insufficiency, in accordance with biologic data and physiopathologic mechanisms.