Background: Preclinical study and human patch tests indicate polyolprepolymer-2 may reduce cutaneous tretinoin-induced irritation. Objective: This study compared the clinical efficacy and safety of a 0.025% tretinoin cream containing polyolprepolymer-2 and its vehicle to a commercially-available 0.025% tretinoin cream. Methods: In this 12-week multicenter, double-blind, parallel group study in patients with mild to moderate acne, objective lesion counts and the investigators’ global evaluations evaluated efficacy. Subjective evaluations of skin irritation were used to study safety. Results: A total of 271 patients were enrolled. The active treatments demonstrated comparable efficacy that was statistically significantly greater than that of the vehicle. Safety evaluations of cutaneous and noncutaneous adverse events also indicated comparable results of the active treatments. Conclusion: The commercially-available 0.025% tretinoin cream and the 0.025% tretinoin cream containing polyolprepolymer-2 demonstrated comparable efficacy and safety. (J Am Acad Dermatol 1998;38:S24-30.)