Oral doxepin was shown to reduce chronic pruritus due to sulfur mustard. The present study compared the effects of topical doxepin 5% with betamethasone 1% for the treatment of pruritus in veterans exposed to sulfur mustard. This investigator-blinded, randomized, clinical trial was conducted in an outpatient dermatology clinic. Seventy-five men who were exposed to sulfur mustard 23 to 28 years ago during the Iran-Iraq war who complained of pruritus were randomized to receive doxepin cream 5% (n = 40) or betamethasone cream 0.1% (n = 35) twice a day for 6 weeks. Pruritus severity and Dermatology Life Quality Index (DLQI) were evaluated before and after each treatment. Both groups showed significant improvement regarding pruritus (P < .05), burning sensation, skin dryness (P < .001), and skin scaling (P < 0.05). The lesions of all regions significantly reduced after treatments (P < .05), except those on the head, face, and genitalia. Pruritus, visual analog scores, and DLQI significantly decreased (P < .01, P < .01, and P < .001, respectively) in doxepin- and betamethasone-treated groups, and there was no difference between groups. All DLQI subscores decreased after both type of treatments (P < .01). Equal efficacy of doxepin cream and betamethasone suggest that doxepin is a potential alternative to control pruritus caused by sulfur mustard in exposed veterans.