Background: Twenty-nail dystrophy (TND) is an acquired idiopathic disease characterized by dull, thin, lusterless, and fragile nails with fissuring, small regular pits, and excessive longitudinal ridging. Although various treatment modalities have been performed in order to treat TND, the effects of these treatments are controversial. Objective: To evaluate the effectiveness of oral cyclosporine in TND. Methods: A total of 38 patients with TND were treated with combination therapy using oral cyclosporine with a pantothenic acid complex-based dietary supplement (Pantogar; Merz Pharmaceuticals GmbH, Germany), whereas 44 patients were treated with the pantothenic acid complex-based dietary supplement alone. The therapeutic efficacy in each group was retrospectively evaluated using medical records and clinical photographs. Results: The cyclosporine therapy group had significantly more patients whose improvement was rated as almost clear, marked, or moderate compared to the control group (p＜0.001). While the mean CHATS (Color, Hyperkeratosis, Area, Thickness, Separation) score of the cyclosporine therapy group was decreased by 13.45 (from 30.95 to 17.5) after treatment, the mean CHATS score of the control group was only decreased by 8 (from 29.43 to 21.43, p＜0.001). Moreover, greater Dermatology Life Quality Index changes after treatment were observed in the cyclosporine therapy group (p=0.085). Conclusion: Oral cyclosporine can be a valuable therapeutic option in patients with TND.