Context - Gender dysphoria refers to distress caused by the incongruence between the biological sex and the individual’s self-identified gender. Transsexual persons are often treated with cross-sex hormonal therapy in order to reduce biological hormones levels and develop phenotypical features concordant with their gender identity. The goal of treatment in Female to Male (FtM) transsexuals is to stop menses and induce virilization. These changes induced with hormone treatment have been reported to reduce psycological discomfort and improve the quality of life. Objective - To evaluate safety of five years testosterone administration in FtM subjects. Patients - Forty Female to Male subjects aged 21-42 years were included in this study. All patients were studied at baseline, before the administration of hormonal therapy, at year 1 and year 5 of testosterone treatment. All subjects were naïve of T at admission. Interventions - Twentyfive patients (TU group) were treated with testosterone undecanoate 1000 mg/12-16 weeks and 15 subjects (TE group) with testosterone enanthate 250 mg/21-28 days. Methods - Anthropometric evaluation, blood pressure monitoring, body composition study and blood test were performed at baseline, year 1 and 5 of treatment. Body composition was measured by dual X-ray absorptiometry. Framingham risk score was assessed to estimate the patient risk of developing cardiovascular disease. Visual analog scale (VAS) was used for the determination of satisfaction at baseline and during the study period. Results - High-density plasma lipoprotein levels declined significantly while low-density lipoprotein and total cholesterol concentrations increased significantly, but always remaining with in normal range. Blood pressure did not change significantly from baseline and no modifications were reported in fasting glucose, insulin and HOMAr. Body weight, BMI and waist-hip ratio (WHR) increased significantly in all group. Lean body mass significantly increased and fat mass decreased in both groups. No significant changes in Framingham risk score were observed.All subjects were highly satisfied (VAS score) with T treatment with no differences between the two groups. Conclusions - Our data suggests that five-years testosterone administration in FtM persons is safe, regardless of the testosterone formulation used and improves quality of life in these subjects.