A family with a pronounced history of venous thrombotic disease is described. Several members were found to have reduced antithrombin III levels. Heparin cofactor activity was reduced in the antithrombin III-deficient plasma. The proposita, who presented with bilateral iliofemoral vein thrombosis early in pregnancy, was treated initially with heparin, and after the 12th week of pregnancy was maintained on oral anticoagulants until she was 38 weeks pregnant. Heparin was then given and continued throughout the delivery period and for 10 days postpartum with no evidence of recurrent thrombosis. The effect of infusing 5 units of fresh frozen plasma on the antithrombin III level and the response to heparin were minimal and short-lived. Oral anticoagulatns produced a rise in the antithrombin III level. These results demonstrate the importance of maintaining antithrombin III-deficient subjects on long-term oral anticoagulant therapy.