Background Inverse psoriasis can be difficult to treat because of the high sensitivity of intertriginous areas to cutaneous side effects, such as irritation and striae. Pimecrolimus, a well-tolerated, nonatrophogenic, skin-selective inflammatory cytokine inhibitor, has been shown to be effective in the treatment of psoriasis when applied topically under occlusion. Objective This study evaluated the efficacy and safety of pimecrolimus cream 1% versus vehicle twice a day in the treatment of inverse psoriasis. Methods This was a double-blind, randomized, vehicle-controlled study in 57 patients with moderate to severe inverse psoriasis. Patients were evaluated using Investigator's Global Assessment of overall severity, Target Area Score, and Patient Self-Assessment. Results A significant between-group difference was observed early on, with 54% of the pimecrolimus group versus 21% of the vehicle group having an Investigator's Global Assessment score of 0 or 1 (clear or almost clear) at week 2 ( P =.0169). By week 8, 71% of the pimecrolimus group had an Investigator's Global Assessment score of 0 or 1. Change from baseline in Target Area Score was −2.4 (pimecrolimus group) compared with −0.7 (vehicle) at day 3 ( P P =.0007). Adverse events were similar between groups. Conclusion Pimecrolimus cream 1% is an effective treatment for inverse psoriasis with a rapid onset of action, and is safe and well-tolerated.