Background: Corticosteroids, zinc paste and eosin 2% are well-known topical agents for the treatment of moderate to severe diaper dermatitis. Among these treatments, the aqueous solution of eosin 2% is extensively used in several European countries, but not in the USA or Israel. Objective: To assess the therapeutic efficacy of eosin 2% solution compared to the other treatment modalities for diaper dermatitis. Methods: Fifty-four infants with diaper dermatitis, recruited from hospital wards and community clinics, were randomly assigned to three treatment groups: zinc oxide paste (containing allantoin 0.5%, cod liver oil 17% and zinc oxide 47epercnt;); clobetasone butyrate 0.05%, and aqueous solution of eosin 2%. The severity of the disorder was graded on a 6-point scale by observation and quantitative measurement of the lesions. The groups were compared for rates and time to heal. Due to the red color of eosin, a double-blind controlled study was impossible. Results: Following 5 days of treatment, the rate of complete healing in the group treated with eosin (61%) was significantly higher (p = 0.0479) than that in the zinc oxide paste and corticosteroid groups (22 and 33%, respectively). Furthermore, in cases of partial healing, the degree of improvement was higher in the eosin group than the other two (p = 0.0205). The fastest improvement was observed in the group treated with corticosteroid cream. Conclusion: Considering the potential hazards of topical corticosteroids and the greater overall efficacy of eosin 2% solution, we suggest that eosin is the preferred treatment for diaper dermatitis.