Background: Vitiligo is a chronic depigmenting disorder characterized by the destruction of melanocytes, resulting in progressive hypopigmented macules. Although oral corticosteroids and immunomodulators are widely used for disease control, their comparative efficacy and safety profiles require further evaluation.

Aim: This study aimed to compare the efficacy, safety, and cost-effectiveness of oral Levamisole and Betamethasone in the management of localized vitiligo.

Methodology: A prospective, randomized, open-label study was conducted on 80 patients with localized vitiligo at a tertiary care center in India. Patients were randomly assigned to receive either Levamisole 150 mg or Betamethasone 5 mg, both administered orally on two consecutive days per week for six months. Clinical response was assessed monthly using VASI (Vitiligo Area Scoring Index), VIDA (Vitiligo Disease Activity), and standardized digital photography. Statistical analysis was performed using Student’s t-test and Chi-square test; p < 0.05 was considered statistically significant.

Results: Both groups demonstrated statistically significant improvement in VASI scores: Levamisole group (0.87 ± 0.79 to 0.67 ± 0.65, p < 0.004) and Betamethasone group (1.07 ± 0.61 to 0.86 ± 0.54, p < 0.002). The response rate was slightly higher with Betamethasone (64.86%) versus Levamisole (59.45%). Lesion progression was arrested in 59.5% (Levamisole) and 61.5% (Betamethasone) of patients. Adverse effects were more common with Betamethasone (28.2%) compared to Levamisole (18.9%). Treatment cost was significantly lower with Betamethasone.

Conclusion: Both Levamisole and Betamethasone were effective in controlling vitiligo progression and inducing repigmentation. While Betamethasone was more cost-effective, Levamisole exhibited a better safety profile. Individualized therapy selection is recommended based on cost, tolerability, and patient-specific factors.