An open, randomized study was performed at 18 European centres to compare the efficacy, safety and tolerance of oral fluconazole with oral polyenes for the prophylaxis of fungal colonization and infection in adults at high risk of developing neutropenia. Five hundred and thirty-six hospitalized patients with malignant disease, about to receive chemotherapy, radiotherapy, or bone marrow transplantation, and who were already neutropenic or were expected to develop neutropenia were included in the study. Before therapy or transplantation, patients commenced either oral fluconazole therapy (50 mg/day as a single dose) or oral polyenes therapy (amphotericin B 2 g/day and/or nystatin 4 x 10(6) units/day in four or more divided doses), for a mean of 29.3 days and 31.3 days, respectively. After baseline clinical and mycological testing, patients were re-evaluated at least weekly during prophylaxis, at the end of prophylaxis and two to six weeks later to identify proven or suspected fungal infection and to determine rates of colonization with fungi. Fungal infection was diagnosed in 41 of 511 evaluable patients, 10 (3.9%) of 256 in the fluconazole group and 31 (12.2%) of 255 in the polyene group (P = 0.001). This total included four patients (1.6%) in the fluconazole group who developed oropharyngeal candidiasis compared with 22 (8.6%) in the polyene group (P < 0.001). Systemic infections comprised 6 (2.3%) in the fluconazole group and 9 (3.5%) in the polyene group (P = not significant), and included three Candida krusei infections in each group. Parenteral amphotericin B therapy was given empirically for persistent fevers in an additional 62 (24.2%) patients receiving fluconazole and 59 (23.1%) receiving polyenes (P = not significant). Colonization with fungi was generally similar in each treatment group, although an increased proportion of patients receiving fluconazole developed colonization of the faeces (P < 0.01). Adverse reactions, possibly related to treatment, were recorded in 15 (5.6%) of 269 patients in the fluconazole group and 14 (5.2%) of 267 in the polyene group; these necessitated discontinuation of therapy in seven patients in each group. Once-a-day fluconazole was therefore more effective than oral polyenes for the prevention of oropharyngeal fungal infection and as effective for the prevention of infections at other sites in patients with neutropenia.