Management of oral candidiasis depends on an accurate diagnosis, identification and elimination of predisposing factors, and, often, use of antifungal agents. Chronic hyperplastic candidosis (CHC) is considered a premalignant lesion of the oral mucosa, occurring as speckled or homogeneous white lesions. If the lesions are untreated, a minor proportion may become dysplastic and progress to carcinoma. The traditional treatment of this lesion is based on the use of antifungal agents. The aim of this study was to examine the efficacy of 0.18% isotretinoin for treatment of nystatin-resistant candidiasis. Isotretinoin was administered topically twice a day for one month to six patients affected by nystatin-resistant CHC. In all six patients, daily antimycotic topical therapy with nystatin for 30 days had failed to resolve the candidal stomatitis. After one month of isotretinoin treatment, five of the six patients were negative for Candida, whereas in untreated control patients the situation was unchanged. Only one patient with suspected sicca syndrome was found to have oral Candida 15 days after the last administration of isotretinoin. None of the patients had any complaints about the medication. These findings suggest that 0.18% isotretinoin applied twice a day for one month is able to suppress nystatin-resistant candidiasis.