BACKGROUND: The first gel formulation of ketoconazole has been tested in 2-week treatment courses. OBJECTIVE: To evaluate the efficacy and safety of a new, once-daily, 2-week ketoconazole 2% gel treatment in moderate to severe seborrheic dermatitis. METHODS: Four hundred fifty-nine subjects with moderate to severe seborrheic dermatitis were randomized to receive ketoconazole 2% gel or vehicle gel once daily for 14 days. The primary efficacy was the proportion of successfully treated subjects at day 28 (cleared and almost cleared). RESULTS: A significantly greater percentage of subjects were successfully treated with ketoconazole 2% gel compared with vehicle (25.3% vs. 13.9%, P = .0014). Ketoconazole 2% gel improved erythema, scaling (P = .0022 vs. vehicle), and pruritus. Mean overall symptom severity was reduced by 53% and 39% with ketoconazole gel and vehicle, respectively. Adverse events were few, generally mild or moderate, and similar between treatment groups. CONCLUSION: Once-daily ketoconazole 2% gel is an effective,well-tolerated, convenient, and cosmetically acceptable treatment for moderate to severe seborrheic dermatitis.