Background: It is not unusual for men over 60 years of age to have serum testosterone levels below the lower limits of younger men, prompting a diagnosis of hypogonadism. This study evaluated safety, efficacy, and pharmacokinetics of oral enclomiphene citrate as an alternative to currently available androgen replacement therapies. Methods: Fifty-two subjects were randomized to oral enclomiphene citrate (12.5 mg, 25 mg, or 50 mg), topical testosterone gel (5 g) or oral placebo daily for 14 days. Pharmacodynamic profiles of total testosterone (TT) were obtained on day 1 and day 14 after dosing. Subjects were assessed in a follow-up visit 7-10 days after the final dose. Additional subjects were rescreened and added for a 10-g dose cohort. Results: After 14 days, there was a significant, dose-dependent rise in TT across all doses of enclomiphene citrate and topical testosterone, but not placebo. Supraphysiologic levels of TT were observed in topical testosterone-treated subjects, whereas TT levels were maintained within a desirable range of 400 to 700 ng/dL in enclomiphene citrate-treated subjects. Enclomiphene citrate 25 and 50 mg doses and topical testosterone (10 g) treatment elevated free testosterone levels more at day 14 compared with day 1 than did placebo. Topical testosterone (5 g) was associated with disproportionate increase in dihydrotestosterone (DHT) relative to TT, while enclomiphene citrate resulted in a modest decrease. Enclomiphene citrate was rapidly absorbed and had an elimination half-life of about 10 hours. A non-dose-dependent steady-state level was maximal at the 25 mg dose. The effects of enclomiphene citrate were sustained with daily dosing. Conclusions: Enclomiphene citrate increased total and free testosterone without increasing DHT disproportionately. Changes in luteinizing hormone, follicle stimulating hormone, and the DHT/TT ratio with enclomiphene citrate suggest it normalizes endogenous testosterone production pathways and restores normal testosterone levels in men with secondary hypogonadism within 14 days.