In a large retrospective study of thrombophilic families, we analyzed 405 relatives of patients, hypothesizing that hyperhomocysteinemia and elevated factor VIII levels are closely related. Median factor VIII levels in hyperhomocysteinemic relatives were 169 IU/dL, compared with 136 IU/dL in normohomocysteinemic relatives (p =0.007), and were more often elevated (>150 IU/dL; p =0.006). Hyperhomocysteinemia was associated with an increased risk of venous and arterial thrombosis; relative risk (RR) 2.6 (CI 1.3-4.8) and 3.7 (CI 1.5-8.4) respectively. Relatives with elevated FVIII were also at risk; RR 2.3 (CI 1.4-4.0) for venous thrombosis and 2.3 (CI 1.0-5.1) for arterial thrombosis. After excluding all relatives with elevated factor VIII, RR for hyperhomocysteinemia and venous thrombosis dropped to 1.3 (CI 0.2-9.8) and no relatives had arterial thrombosis. We conclude that it is likely that the increased risk of venous and arterial thrombosis in hyperhomocysteinemia is mainly related to elevated FVIII levels.