Optimal therapy for oropharyngeal candidiasis, a common infection in immunocompromised patients, has yet to be clearly defined. Topical therapy is usually poorly tolerated; ketoconazole is effective but absorption is highly variable. New antifungal agents have been developed to increase the therapeutic options. Fluconazole is active against yeasts, is available in both oral and intravenous formulations, and has a pharmacokinetic profile different from that of ketoconazole. This randomized double-blind study evaluates systemic antifungal therapy with fluconazole (100 mg daily) or ketoconazole (400-mg daily) for oropharyngeal candidiasis in patients with cancer. Clinical cure was observed in 15 of 19 and 14 of 18 patients treated with fluconazole and ketoconazole, respectively. Eradication of pathogenic yeasts ws documented for 10 patients in both groups. The rates of relapse were similar, but relapse occurred earlier in patients in the ketoconazole group. Overall, this study demonstrates the value of a dosage of 100 mg of fluconazole or of 400 mg of ketoconazole daily for the management of oropharyngeal candidiasis in patients with cancer.