Background: Highly variable results of topical immunotherapy with Diphencyprone (DPC) in the treatment of Alopecia areata have been reported so far. Objective: The purpose of this study was to evaluate the efficacy and tolerability of DPC in the treatment of severe and chronic chronic Alopecia areata. Patients and Methods: 28 patients (16 female and 12 male, 10-35 years old, mean age 25 years) with chronic and/or extensive Alopecia areata were enrolled in an open-label clinical trial. After sensitization with 2% DPC, progressively higher concentrations beginning at 0.001% were applied weekly for 6 months to one side of the scalp. The maximum concentration of DPC was 2%. Results: 27 of 28 patients completed therapy. The overall response rate was 81.5% (22 cases). Complete response (90%-100% terminal hair re-growth) was obtained in 22.2% (6 cases) and partial response (10%-90% terminal hair re-growth) in 59.3% (16 cases), and 18.5% (5 cases) showed no regrowth. In all patients an eczematous reaction consisting of erythema, itching, and scaling at the site of application was observed. Other observed side effects included occipital lymphadenopathy in 40.7% (11 cases), severe eczema/blister formation in 40.7% (11 cases), hyperpigmentation in 18.5% (5 cases). Notably, partial recurrence was observed in 66.7% (18 cases) of these patients after 6 to 12 months of follow up. Conclusion: Topical DPC treatment for Alopecia areata is an effective therapy with a relatively high relapse rate.