The feasibility of using the castrated Yucatan minipig as a hypogonadal animal model to investigate the transdermal controlled systemic delivery of testosterone was studied. During a 24 h application of a testosterone transdermal delivery device (T-TDD), serial blood samples were withdrawn from the minipigs, without anesthesia, at predetermined time intervals and the plasma concentrations of testosterone as well as its major metabolites, dihydrotestosterone and estradiol, were assayed by radioimmunoassay. The compartmental pharmacokinetic modeling analysis of the plasma profiles of total testosterone indicated that as much as 92% of the total testosterone dose released from the T-TDD had been delivered transdermally into the systemic circulation during the initial rapid input period (the first 11 h of the application), while only 8% was delivered during the slow input period (up to 23 h). Good correlation was observed between the in vivo input doses [1.9 (±0.2), 4.8 (±0.2) and 6.4 (±0.5) mg/day], determined by the Wagner-Nelson equation, and the daily doses released [1.9± (0.2), 4.7 (±0.2) and 6.6 (±0.5) mg/day, respectively, for 1, 2, and 3 units of T-TDD]. While the in vivo rate of input in the castrated minipigs was observed to be similar to that in hypogonadal men treated with the T-TDD during the first 8 h period, the input rate was found to be slower during the last 12 h. The agreement could suggest that the mechanism for the transdermal systemic delivery of testosterone in the castrated minipig could be similar to that in the hypogonadal men. However, the plasma testosterone profiles attained in the castrated minipigs were observed to be similar to, but slightly lower than that in the hypogonadal men reported in the literature. The Δ C max (baseline normalized peak plasma concentration) and Δ C avg (baseline normalized average plasma concentration) data in the castrated minipigs were 40 and 44%, respectively, of that in hypogonadal men. The ~2.4 fold lower values in Δ C max and Δ C avg data could result from the difference in the clearance rate of testosterone which is ~2.8 fold higher in minipigs than in the human. Despite the difference in clearance rate, the castrated minipigs could be a suitable large animal model for studying the pharmacokinetics of testosterone delivered transdermally in humans with hypogonadism.