Introduction Data on the effects of cross‐sex hormone therapy (CHT) are limited due to the low prevalence of gender dysphoria, small number of subjects treated at each center, lack of prospective studies, and wide variations in treatment modalities.

Aim The aim of this study is to report the short‐term effects of CHT on hormonal and clinical changes, side effects, and adverse events in trans men (female‐to‐male gender dysphoric persons) and trans women (male‐to‐female gender dysphoric persons).

Methods This was a multicenter 1‐year prospective study in 53 trans men and 53 trans women. Trans men received injections of testosterone undecanoate every 3 months. Trans women younger than 45 years received 50 mg cyproterone acetate (CA) and 4 mg estradiol valerate daily, whereas those older than 45 years received 50 mg CA daily together with 100 μg/24 hours transdermal 17‐β estradiol.

Main Outcome Measures Sex steroids, prolactin, liver enzymes, lipids, hematocrit, blood pressure, anthropometrics, Ferriman and Gallwey score, and global acne grading scale were measured. Side effects, adverse events, and desired clinical changes were examined.

Results No deaths or severe adverse events were observed. Two trans men developed erythrocytosis, and two had transient elevation of the liver enzymes. Trans men reported an increase in sexual desire, voice instability, and clitoral pain (all P ≤ 0.01). Testosterone therapy increased acne scores, facial and body hair, and prevalence of androgenetic alopecia. Waist–hip ratio, muscle mass, triglycerides, total cholesterol (C), and LDL‐C increased, whereas total body fat mass and HDL‐C decreased. Three trans women experienced transient elevation of liver enzymes. A significant increase in breast tenderness, hot flashes, emotionality, and low sex drive was observed (all P ≤ 0.02). Fasting insulin, total body fat mass, and prolactin levels increased, and waist–hip ratio, lean mass, total C, and LDL‐C decreased.