41 subjects with highly elevated IgG anticardiolipin antibody (aCL) titers (> 30 GPL-U/ml) were retrospectively evaluated regarding underlying disease, clinical symptoms, and in particular the influence of drugs on aCL titer and clinical symptoms. Whereas 31/41 (76%) fulfilled the criteria for an antiphospholipid antibody syndrome (APS), 10 (24%) did not. About half (47%) of the patients had an autoimmune disease (mainly systemic lupus erythematosus). 26 (63%) had had recurrent thrombophilic events, 3 (7%) recurrent spontaneous abortions and 10 (24%) associated thrombocytopenia. 8/34 (23%) subjects followed up over 6-42 months had a thrombophilic complication again. 6/16 (37%) developed deep venous thrombosis in spite of oral anticoagulation (INR 1.5-3.0), one of three under acetylsalicylic acid treatment and only one subject without therapy. ACL titer decreased (> 12 U/ml) in 20/34 subjects (59%) during the follow-up period, mainly in patients under immunosuppressive treatment due to the underlying autoimmune disease. In comparison with 5/14 subjects (36%) with consistently high aCL, only 3/20 (15%) with decreasing aCL developed thrombosis. Patients treated by immunosuppressive agents had a higher incidence of decreasing aCL than those without. This investigation indicates that a high titer of aCL in asymptomatic subjects does not justify prophylactic anticoagulation therapy. However, if a history of recurrent deep venous thromboses or pulmonary embolisms is established, long-term anticoagulation therapy should be maintained at or above the international normalized ratio (INR) of 3. ACL titers in subjects with an autoimmune disease may decline, as a result of immunosuppressive treatment or otherwise, and this decline is associated with a lower incidence of thrombophilic disorders.