We assessed previously undiagnosed thrombophilia-hypofibrinolysis in 11 testosterone (T)-taking men, five of whom developed deep venous thrombosis (DVT), four pulmonary embolism, one spinal cord infarction, and one osteonecrosis 3.5 months (median) after starting T gel (50-160 mg/day) or T intramuscular (50-250 mg/week). In the order of referral because of thrombosis after starting T, thrombophilia-hypofibrinolysis was studied in 11 men, and, separately, in two control groups without thrombosis - 44 healthy normal male controls and 39 healthy men taking T. Nine men had DVT or DVT-pulmonary embolism after 3.5 months (median) on T, one spinal cord infarction after 5 days on T, and one had osteonecrosis (knee and then hip osteonecrosis after 6 and 18 months on T). Four of the 11 men (36%) had high factor VIII (≥150%) vs. one of 42 (2%) controls (P = 0.005), and vs. one of 25 (4%) T-controls, (P = 0.023). Of the 11 men, two (18%) had factor V Leiden heterozygosity vs. none of 44 controls, (P = 0.04) and vs. none of 39 T-controls(P = 0.045). Of the 11 men, three had 4G4G plasminogen activator inhibitor-1 homozygosity, one prothrombin G20210A heterozygosity, one low protein S, and one high factor XI. When T was continued, second DVT-pulmonary embolism recurred in three of 11 men despite adequate anticoagulation. T interacts with thrombophilia-hypofibrinolysis leading to thrombosis. Men sustaining DVT-pulmonary embolism-osteonecrosis on T should be studied for thrombophilia. Continuation of T in thrombophilic men appears to be contraindicated because of recurrent thrombosis despite adequate anticoagulation. Before starting T, to prevent T-associated thrombosis, we recommend measures of factor V Leiden, factor VIII, and the prothrombin gene.