We compared the efficacy of intravenous fluconazole (80 mg/kg of body weight per day) with that of amphotericin B (1 mg/kg/day) for the long-term treatment of endophthalmitis in rabbits with disseminated candidiasis. After 17 days of therapy, fluconazole decreased the fungal colony counts of the choroid-retinas significantly more than did the saline control (P < 0.5); however, after 24 days of fluconazole therapy, this treatment effect was lost and fluconazole was no more effective than saline. In contrast, treatment for 24 days with amphotericin B reduced the vitreous and choroid-retina fungal colony counts significantly more than either fluconazole or saline (P < 0.05 for both treatment groups). After 17 days of therapy, indirect ophthalmoscopy revealed less severe eye involvement in both antifungal treatment groups than in saline controls; however, this difference reached statistical significance only for the amphotericin B-treated rabbits (P < 0.05). Also, there was a trend towards worsening eye lesions, as seen by indirect ophthalmoscopy, in the fluconazole-treated rabbits after 24 days of therapy, which roughly paralleled the quantitative culture results. Despite the presence of negative choroid-retina cultures, some rabbits in all treatment groups had persistently visible eye lesions, indicating that ophthalmoscopic resolution of Candida endophthalmitis may lag behind lesion sterilization. Amphotericin B was superior to fluconazole in the treatment of Candida endophthalmitis in this model.