Introduction Vitiligo is an acquired pigmentary disorder of the skin and mucous membranes which is characterized by circumscribed depigmented macules and patches. Vitiligo is a progressive disorder in which some or all of the melanocytes in the affected skin are selectively destroyed. Around 0.5-2% of the world population is affected by vitiligo and the average age of onset is 20 years. The objective of the study was to evaluate the efficacy of tacrolimus versus clobetasol in the treatment of vitiligo. It is an open randomized control trial conducted in the Department of Dermatology, Nishtar Hospital, Multan for six months.  Methods One hundred sixty-two patients of vitiligo were included in the study. The disease was diagnosed on basis of clinical features and the Standard Assessment scale proposed by Hossain which was used to monitor and grade the response. Patients were randomly allocated into two groups by lottery method having 81 patients in each group. Group A was given tacrolimus whereas Group B was given clobetasol. Patients were followed up every four weeks. On the 12 week of treatment, effectiveness was assessed by measuring the Assessment scale proposed by Hossain. The results of the two groups were then compared. Results Sixty-three patients (38.9%) were males whereas 99 patients (61.1%) were females. The mean age of the patients included in the study was 29.68 + 8.162 years. The mean weight of the patients was 62.25 + 9.529 Kg. Out of 162, treatment was effective in 89 patients (54.9%) whereas in 73 patients (45.1%) the treatment was ineffective. In Group A (tacrolimus), 42 patients (51.9%) had effective treatment (on the complete resolution of symptoms) whereas 39 patients (48.1 %) had ineffective treatment. In Group B (clobetasol), 47 patients (58%) had effective treatment, and the rest (34, 42%) had ineffective treatment. A Chi-Square test was applied to compare the efficacy of the two groups. There was no statistically significant difference in both the groups in terms of efficacy. Group B was numerically superior in terms of effective treatment (47 versus 42) but not superior statistically. Conclusion Comparison of tacrolimus and clobetasol in patients of vitiligo showed no significant difference in the efficacy of the two groups. It can be concluded that tacrolimus may be considered superior to corticosteroids as its local and systemic adverse effects are less.