BACKGROUND: A novel tretinoin preparation uses polyolprepolymer-2, a compound designed to reduce skin irritation by helping retain drugs on and in the surface layers of the skin. OBJECTIVE: We used patch testing to measure the effect of polyolprepolymer-2 on tretinoin-associated irritation. METHODS: Two patch test studies were conducted. The first assessed the effect of polyolprepolymer-2 by comparing commercially-available tretinoin formulations with respective polyolprepolymer-containing formulations of 0.025% tretinoin gel and 0.025%, 0.05%, and 0.1% tretinoin creams. The second assessed the effect of the polyolprepolymer-2 concentration on the potential decrease in irritation by comparing: (1) a commercially-available tretinoin cream with prototype tretinoin creams containing 20% polyolprepolymer-2 at three different concentrations of tretinoin (0.025%, 0.05%, and 0.1%); and (2) the effect of three different polyolprepolymer-2 concentrations (10%, 15%, and 20%) in prototype tretinoin creams on cumulative irritation. Patch agents were assigned to subjects according to a randomization schedule, and during a period of 5 days each subject received three 24-hour exposures to the test materials. Twenty-four hours elapsed between old patch removal and new patch application. RESULTS: In the first study, the tretinoin gel and cream containing polyolprepolymer-2 caused significantly less irritation than all equivalent formulations of the commercially-available tretinoin gel and creams except the 0.025% cream formulation. Irritation scores were not significantly different in terms of irritation in the 0.025% creams although scores did indicate a trend towards lower irritation with 0.025% tretinoin cream containing polyolprepolymer-2. In the second study, the tretinoin gel containing polyolprepolymer-2 and the three tretinoin prototype creams also containing polyolprepolymer-2 caused significantly less irritation than comparable concentrations of the commercially-available tretinoin. In addition, the 0.025% tretinoin gel formulation containing polyolprepolymer-2 was no more irritating than the commercially-available 0.025% tretinoin cream. CONCLUSION: Tretinoin formulations containing polyolprepolymer-2 are, in general, less irritating than the currently marketed tretinoin formulations.