Abstract Background Among all the topical immunomodulators, vitiligo's mainstay therapy includes topical corticosteroids. Many other non‐immune theories have also been suggested for vitiligo's pathogenesis, but the role of oxidative stress has gained more importance in recent years. Objective To compare the effect of topical 0.05% betamethasone vs. catalase/dismutase superoxide (C/DSO). Study design Randomized, matched‐paired, double‐blind trial. Setting Dermatology Section, University of Antioquia, Medellín, Colombia. Subjects Patients (aged > 18 years or between 12 and 18 years) with parent's informed consent, with stable or active bilateral vitiligo. Intervention Topical 0.05% betamethasone or C/DSO. Methods Two lesions similar to each other in size were chosen. All assessments were made by two blinded investigators, and photographs were subjected to morphometry analysis. Main outcome Skin repigmentation by digital morphometry. Results Twenty‐five patients were enrolled in the study (21 women and 4 men). Mean age of participants was 40 years (range: 12–74 years). One patient on C/DSO experienced a mild local erythematous papular rash that self‐resolved. At 4 months of therapy, there was no statistical difference on the percentage of repigmentation between betamethasone and C/DSO (5.63% ± 27.9 vs. 3.22% ± 25.8, respectively, P = 0.758). After 10 months of therapy, the percentage of skin repigmentation increased to 18.5 ± 93.14% with betamethasone and to 12.4 ± 59% with C/DSO, but again, we found no statistical differences ( P = 0.79). Discussion and conclusions Few studies have described objective methods to evaluate repigmentation among vitiligo patients. Digital morphometry provides an objective assessment of repigmentation in vitiligo. Objective vitiligo repigmentation with topical C/DSO at 10 months is similar to topical 0.05% betamethasone. Although a mild adverse effect was related to the use of C/DSO, such finding was not severe enough to discontinue treatment.