In this study, we investigated the effect of prednicarbate, mometasone furoate and betamethasone 17-valerate on total skin thickness over a treatment period of 6 weeks. The study was conducted as a double-blind, placebo-controlled randomized clinical trial with a confirmatory approach. The influence of these drugs on healthy human skin under non-occlusive conditions was assessed by measuring total skin thickness and epidermal thickness using 20 and 50 MHz sonography, respectively. Epidermal surface structure was evaluated using profilometry. Visual assessment addressed signs of atrophy and formation of telangiectasia. The reduction of total skin thickness induced by prednicarbate was clearly less than that caused by betamethasone 17-valerate and mometasone furoate. Prednicarbate led to a higher degree of skin thinning than vehicle. For technical reasons, epidermal thickness could not be reliably evaluated with 50 MHz sonography. Profilometry did not demonstrate any differences between treatments. Visible signs of atrophy or telangiectasia were detected in two subjects each upon betamethasone 17-valerate and mometasone furoate, but not upon prednicarbate or its vehicle. Prednicarbate is a topical glucocorticoid with an improved benefit/risk ratio, as it causes less skin atrophy than the equipotent betamethasone 17-valerate.