Background: Dermatophyte infections of the toenail have been difficult to treat, requiring long courses of therapy and having high recurrence rates. New oral antifungal agents with better outcomes and minimal adverse events are needed. Objective: The purpose of this study was to compare two newer antifungal compounds, terbinafine and itraconazole, for efficacy and safety in toenail onychomycosis caused by dermatophytes. Methods: The study was randomized and double-blind. It compared 12 weeks of continuous oral treatment with terbinafine 250 mg/day or itraconazole 200 mg/day for confirmed toenail dermatophyte onychomycosis. Clinical symptoms and mycologic outcome were assessed at weeks 4, 8, 12, 24, 36, and 48. A total of 372 patients (186 in each group) with dermatophyte infection confirmed by microscopy and culture were included in the intent-to-treat analysis. Results: At week 48, a statistically significantly greater percentage of the terbinafine group than itraconazole group showed negative mycology (73% [119 of 163] vs 45.8% [77 of 168]; p < 0.0001) (difference = 27.2%; 95% CI = [17.0%, 37.3%]). The difference was also confirmed clinically (p = 0.001) in the patients who were clinically cured or had only minimal symptoms at the end of the study (76.2% [125 of 164] vs 58.1% [100 of 172]) (difference = 18.1%; 95% CI = [8.24%, 27.9%]). The geometric mean length of healthy nail of the big toe was significantly greater in the terbinafine than itraconazole group (8.1 vs 6.4 mm; p = 0.026). Tolerability was good to very good in almost 90% of patients in both groups, and all reported adverse events were known for these compounds. Conclusion: Terbinafine produced higher rates of clinical and mycologic cure at follow-up than did itraconazole. (J Am Acad Dermatol 1998;38:S57-63.)