The purpose of this study was to evaluate the efficacy towards acne and the skin surface toxicity ofall-trans-retinoylβ-glucuronide (RBG), a naturally occurring retinoid possessing low cytotoxicity and teratogenicity in animal and cell culture studies. In a double-blind study, 15 acne patients treated with 1.2% RBG cream for 16 weeks showed median reductions of 56%, 25% and 67% in total, inflammatory, and noninflammatory lesions, respectively, whereas the placebo group (14 patients) showed median reductions of 31%, 4% and 62%, respectively. The median reduction in total lesions was highly significant in the RBG group(P= 0.002) but not in the placebo group(P= 0.06). In a second initially double-blind study, ten acne patients treated topically for 26 weeks with 0.16–0.32% RBG cream and five patients with 0.1%all-trans-retinoic acid (Retin-A) showed similar responses, i.e. median reductions in total facial lesions of 70% (P =0.001) and 75% (P= 0.01), respectively. Whereas all subjects treated topically with 0.1% Retin-A showed adverse skin reactions, none of those treated with concentrations of RBG up to 2.4% showed such effects. Thus, RBG seems to be a promising topical treatment for mild to moderate acne, particularly in subjects with highly sensitive skin.