The pharmacokinetics, efficacy, and safety of the Androderm testosterone (T) transdermal system (TTD) and intramuscular T enanthate injections (i.m.) for the treatment of male hypogonadism were compared in a 24-week multicenter, randomized, parallel-group study. Sixty-six adult hypogonadal men (22-65 years of age) were withdrawn from prior i.m. treatment for 4-6 weeks and then randomly assigned to treatment with TTD (two 2.5-mg systems applied nightly) or i.m. (200 mg injected every 2 weeks); there were 33 patients per group. Twenty-six patients in the TTD group and 32 in the i.m. group completed the study. TTD treatment produced circadian variations in the levels of total T, bioavailable T, dihydrotestosterone, and estradiol within the normal physiological ranges. i.m. treatment produced supraphysiological levels of T, bioavailable T, and estradiol (but not dihydrotestosterone) for several days after each injection. Mean morning sex hormone levels were within the normal range in greater proportions of TTD patients (range, 77-100%) than i.m. patients (range, 19-84%). Both treatments normalized LH levels in approximately 50% of patients with primary hypogonadism; however, LH levels were suppressed to the subnormal range in 31% of i.m. patients vs. 0% of TTD patients. Both treatments maintained sexual function (assessed by questionnaire and Rigiscan) and mood (Beck Depression Inventory) at the prior treatment levels. Prostate-specific antigen levels, prostate volumes, and lipid and serum chemistry parameters were comparable in both treatment groups. Transient skin irritation from the patches was reported by 60% of the TTD patients, but caused only three patients (9%) to discontinue treatment. i.m. treatment produced local reactions in 33% of patients and was associated with significantly more abnormal hematocrit elevations (43.8% of patients) compared with TTD treatment (15.4% of patients). Gynecomastia resolved more frequently during TTD treatment (4 of 10 patients) than with i.m. treatment (1 of 9 patients). Although both treatments seem to be efficacious for replacing T in hypogonadal men, the more physiological sex hormone levels and profiles associated with TTD may offer possible advantages over i.m. in minimizing excessive stimulation of erythropoiesis, preventing/ameliorating gynecomastia, and not over-suppressing gonadotropins.