Background: Vitiligo is a relatively common acquired depigmentary disorder affecting approximately 1% of general population. PUVA therapy is the most effective modality and commonly used as the primary treatment of generalized Vitiligo. Objective: To evaluate the synergistic effect of topical Calcipotriol and oral methoxalene plus PUVA in treatment of generalized Vitiligo. Patients and Methods: In this clinical trial, 47 patients with generalized Vitiligo (<40% involvement of skin surface area) were randomly assigned to 2 treatment groups. Both groups were treated with systemic PUVA three times weekly. One group was also treated with topical Calcipotriol (0.005%). Patients were evaluated for treatment response and possible side effects. Results: The mean response rate at the end of the study was 63.9%±24.1 in the Calcipotriol and PUVA group and 60.6%±23 in the PUVA group (P>0.05). The number of PUVA sessions and the mean cumulative UVA dose for maximum response were 96.6±22.7 and 584.1±118.1 J/cm² in the Calcipotriol and PUVA group and 116.3±26.1 and 685.1±168.0 J.cm² in the PUVA group (P<0.05). Conclusion: In patients with generalized Vitiligo, combination of PUVA with Calcipotriol is an effective and safe treatment. This method decreases number of PUVA sessions and UVA dosage compared to PUVA treatment alone and accelerates repigmentation.