The androgenic action of dihydrotestosterone (DHT) is antagonized by agents that compete with testosterone for the 5 alpha-reductase enzyme and by agents that block the binding of DHT to its receptor. The topical synergistic effect of 5 alpha-reductase (5 alpha RI) and androgen receptor inhibitors (ARI) was determined by measurement of the sebaceous gland size (SGS) of the ventral ear skin of the intact, sexually mature male Syrian hamsters. Progesterone (P), a 5 alpha RI, and spironolactone (SL), an ARI, produced a dose responsive decrease in SGS at topical concentrations of 0.01% to 5.0%. At concentrations of 1, 3, and 5%, P and SL combinations produced neither an additive nor synergistic inhibition of SGS. At very low concentrations of up to 0.10%, neither P nor SL alone produced any effect on SGS. When combinations of these two steroids were applied at low concentrations, SGS decreased unilaterally to approximately 50%. This synergy occurred best at a P:SL ratio of 1:2. The lower effective concentrations of P may be explained by its greater percutaneous absorption. Synergy was also demonstrated at low concentrations with other antiandrogens: cyproterone acetate, canrenone, hydroxyflutamide, and N-N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane- 17 beta-carboxamide. The use of anti-androgen combinations at low concentrations is of value because of the decreased risk of systemic side effects while maintaining potent topical efficacy.