Vitiligo is one of the autoimmune skin diseases that destroy the melanocytes of the skin. Moreover, its prevalence varies in different countries and regions.The aim of this study was to compare the effect of Nigella sativa and fish oil on vitiligo lesions of the patients referred to a dermatology clinic.This randomized, double blind clinical trial was conducted in the dermatology clinic of the Imam Khomeini Hospital Ahvaz, Iran, from June to December 2011. We used a randomized simple sampling. From 96 patients with vitiligo, 52 eligible patients were selected and allocated to two groups with equal size. The study medications were applied twice a day by patients on their lesions. After six months, the improvement rate of lesions was assessed by the Vitiligo Area Scoring Index (VASI). Data were analyzed using SPSS v. 15; P value < 0.05 was considered as statistically significant.After six months, a mean score of VASI decreased from 4.98 to 3.75 in patients applying topical Nigella sativa and from 4.98 to 4.62 in those using topical fish oil. Most of the percent improvement observed in upper extremities, trunk, head, and neck of those who received Nigella sativa and head, neck, trunk, and feet of those who received fish oil. No adverse effect was reported by the patients.Nigella sativa oil and fish oil were effective in reduction the size of patient's lesions; however, Nigella sativa was more effective in comparison to the fish oil. Therefore, using Nigella sativa with the major drugs in the treatment of vitiligo is recommended.