Abstract Background Acne vulgaris is a common skin problem that may result in significant scarring and systemic comorbidities. Adverse effects and increasing resistance to available treatments urge the development of new therapeutics. Topical vitamin D analogues have been successfully used in psoriasis; however, the efficacy and safety of calcipotriol as a potential topical treatment of acne is yet to be established. Objectives To evaluate the efficacy and safety of calcipotriol in treating acne compared with adapalene and placebo. Methods Sixty patients with acne were included and randomly divided into two groups of 30 patients each. Group I participants were treated by daily application of calcipotriol 0.005% cream on one facial side vs. placebo (petrolatum) over the other side. Group II were treated by daily application of adapalene 0.1% gel over one facial side vs. calcipotriol on the other. Therapeutic response was evaluated using the Japanese Acne Grading System (JAGS) and through photographic evaluation using Mean Improvement Score by Physician. Results Adapalene-treated skin gave the greatest improvement and the highest patient satisfaction compared with skin treated with calcipotriol or placebo (P = 0.001). Nonetheless, the calcipotriol-treated side showed a significantly greater reduction in post-treatment JAGS score and much greater satisfaction than placebo. As treatment continued, improved tolerability to calcipotriol was noted, with comparable side-effects between the three study arms. Conclusions Calcipotriol seems to be a promising new safe topical therapeutic option for acne. However, adapalene is still superior in efficacy, tolerability and patient satisfaction.