Testosterone therapy in men and women results in decreased high-density lipoprotein cholesterol (HDL) and increased low-density lipoprotein cholesterol (LDL). We sought to determine whether testosterone therapy has this same effect on lipid parameters and adipocyte hormones in female-to-male (FTM) transsexuals. Twelve FTM transsexuals provided a fasting lipid profile including serum total cholesterol, HDL, LDL, and triglycerides prior to and after 1 year of testosterone therapy (testosterone enanthate or cypionate 50–125 mg IM every two weeks). Subjects experienced a significant decrease in mean serum HDL (52 ± 11 to 40 ± 7 mg/dL) (P < .001). The mean LDL (P = .316), triglyceride (P = .910), and total cholesterol (P = .769) levels remained unchanged. In a subset of subjects, we measured serum leptin levels which were reduced by 25% but did not reach statistical significance (P = .181) while resistin levels remained unchanged. We conclude that testosterone therapy in FTM transsexuals can promote an increased atherogenic lipid profile by lowering HDL and possibly reduce serum leptin levels. However, long-term studies are needed to determine whether decreases in HDL result in adverse cardiovascular outcomes.