Current vitiligo treatments are not always satisfactory for both patients and dermatologists. Recently, combination therapies have been introduced in order to obtain better results and reduce risks in the management of the disease. Novel efficacious products are needed to improve the therapeutic possibilities of dermatologists in the respect of safety for the patients. The objective of the present study was to evaluate the effects of a novel topical in a gel formulation containing phenylalanine, cucumis melo extract, and acetyl cysteine in vitiligo. The present study used an open observational study to evaluate the efficacy and safety of the investigated product, given alone or in combination with 311-nm narrow band microphototherapy. Results were compared with those obtained treating a matched patient population with microphototherapy alone and with clobetasol propionate 0.05% ointment alone. One hundred forty-nine patients suffering from symmetrical vitiligo affecting less than 10% of the skin surface were evaluated. Patients affected by acral vitiligo only were excluded from the analysis. Treatment duration was scheduled for 12 weeks. Excellent repigmentation (>75%) was achieved by 38–73% of patients, depending on the treatment regimen. Mild to moderate side effects were observed only in patients treated with clobetasol 0.05% ointment. The tested gel formulation showed a good efficacy in improving vitiligo repigmentation. No side effects were observed.