OBJECTIVE:To evaluate the incidence of venous thromboembolism (VTE) in transsexual patients and the value of screening for thrombophilia in this population. DESIGN:Retrospective cohort study. SETTING:Academic research institution. PATIENT(S):Two hundred fifty-one transsexuals (162 male-to-female [MtF] and 89 female-to-male [FtM] transsexuals). INTERVENTION(S):Screening for activated protein C (aPC) resistance, antithrombin III, free protein S antigen, and protein C deficiency. MAIN OUTCOME MEASURE(S):Incidence of thrombophilic defects and VTE during cross-sex hormone therapy. RESULT(S):Activated protein C resistance was detected in 18/251 patients (7.2%), and protein C deficiency was detected in one patient (0.4%). None of the patients developed VTE under cross-sex hormone therapy during a mean of 64.2 +/- 38.0 months. There was no difference in the incidence of thrombophilia comparing MtF and FtM transsexuals (8.0% [13/162] vs. 5.6% [5/89], respectively). CONCLUSION(S):VTE during cross-sex hormone therapy is rare. General screening for thrombophilic defects in transsexual patients is not recommended. Cross-sex hormone therapy is feasible in MtF as well as in FtM patients with aPC resistance.