Background: Widely accepted in vivo models to evaluate the efficacy of protective creams (PCs) are still missing. Objective: The effect of petrolatum’s ability to protect against irritation was tested in a repetitive irritation test to optimize the concentration of irritants against which PCs are tested and to evaluate the necessary cumulative application time. Methods: On 20 healthy volunteers, the irritants (sodium lauryl sulfate 5% vs 10%, sodium hydroxide 0.5% vs 1%, lactic acid 20% vs 30%, and toluene undiluted) were applied daily for 2 weeks on the ventral forearms after 30 minutes of pretreatment with petrolatum. The irritant cutaneous reactions were quantified by erythema score, transepidermal water loss, and chromametry. Results: For petrolatum, a significant protective effect was obtained against irritation by sodium lauryl sulfate, sodium hydroxide, and toluene in different degrees. Less efficacy was observed against lactic acid. Conclusion: It was concluded that a 1-week period of cumulative irritation is enough to evaluate the efficacy of PCs against most irritants, even if lower concentrations of irritants are used. (J Am Acad Dermatol 1999;40:590-6.)