The Vitamins and Thrombosis (VITRO) study investigated the effect of homocysteine lowering by daily supplementation of B vitamins on the risk reduction of deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients between 20 to 80 years old with a first objectively confirmed proximal DVT or PE in the absence of major risk factors and a homocysteine concentration above the 75th percentile of a reference group were asked to participate (hyperhomocysteinemic group). A similar study was conducted in a random sample of patients with a homocysteine below the 75th percentile of the reference group (normohomocysteinemic group). After informed consent was obtained, patients were randomized to daily multivitamin supplementation (5 mg folic acid, 50 mg pyridoxine, and 0.4 mg cyanocobalamin) or placebo and were followed for 2.5 years. End points were objectively diagnosed recurrent DVT or PE. A total of 701 patients were enrolled (360 in the hyperhomocysteinemic and 341 in the normohomocysteinemic group). The number of recurrent events of venous thrombosis was 43 of 353 in the vitamin group (54/1000 py) and 50 of 348 in the placebo group (64/1000 py). The hazard ratio associated with vitamin treatment was 0.84 (95% CI, 0.56-1.26): 1.14 (95% CI, 0.65-1.98) in the hyperhomocysteinemic group and 0.58 (95% CI, 0.31-1.07) in the normohomocysteinemic group. The results of our study do not show that homocysteine lowering by B vitamin supplementation prevents recurrent venous thrombosis.