This study compared topical pimecrolimus with betamethasone in the treatment of pruritus and chronic skin lesions due to sulfur mustard exposure. Seventy male chemical-injured war veterans participated in this investigator-blinded clinical trial. They were randomized to receive pimecrolimus cream 1% (n = 35) or betamethasone cream 0.1% (n = 35) two times a day for 6 weeks. Dermatological examination and assessment of pruritus severity by a pruritic score questionnaire and visual analogue scale were done before and after the treatment course. A significant decrease (P < 0.05) in pruritus, burning sensation, and skin dryness was shown in both groups after the treatment. However, the severity of hyper- and hypopigmentation, vesicle, erythema, fissure, lichenification and excoriation did not decrease significantly in either group (P > 0.05). Mean (+/- standard deviation) pruritic scores at baseline for the pimecrolimus and betamethasone groups were 30.4 (+/- 8.0) and 33.6 (+/- 7.2), respectively (P = 0.103). These scores decreased to 18.8 (+/- 4.8) in the pimecrolimus and 20.8 (+/- 4.0) in the betamethasone groups after treatment; both showed a statistically significant decrease (P < 0.001). Change of pruritus score from baseline to after the treatment course was not statistically different between the two groups (P = 0.502). No serious side-effects were reported during the course of the treatment. Topical pimecrolimus 1% was as effective as betamethasone cream 0.1% in controlling pruritus, burning sensation and skin dryness of sulfur mustard-exposed patients.