Novel tretinoin cream and gel formulations have been developed that incorporate polyolprepolymer-2, which is a material designed to help retain drug molecules in and on the skin when applied in topical vehicles. The results of preclinical and clinical investigations have confirmed the beneficial impact of such a vehicle on tretinoin tolerability. In vitro studies with selected polyolprepolymer-containing formulations have reduced initial and cumulative tretinoin percutaneous penetration, and guinea pig studies showed that the gel formulation containing polyolprepolymer-2 caused less erythema and edema than did the corresponding commercially-available tretinoin gel formulation. Human studies with tretinoin containing polyolprepolymer-2 have consistently demonstrated a favorable tolerability profile when compared with commercially-available tretinoin. Use of the polyolprepolymer-2–containing tretinoin formulation in human studies has resulted in reductions in peeling — a problem commonly associated with use of standard tretinoin formulations. These reductions in irritation have not been at the expense of efficacy; acne clinical trial results indicate comparable effectiveness between tretinoin containing polyolprepolymer-2 and commercially-available tretinoin. (J Am Acad Dermatol 1998;38:S5-10.)