Purpose: The purpose of this phase 2 study was to determine the potential efficacy and safety of systemic alpha interferon in the treatment of subfoveal choroidal neovascularization associated with age-related macular degeneration or ocular histoplasmosis. Method: Subcutaneous alpha interferon was administered to 24 patients (24 eyes), and they were prospectively studied. Alpha interferon was administered subcutaneously four times daily at a dose of 3 X 10 6 U/m 2 (average total dose, 204 MU). The studied parameters included best-corrected visual acuity, membrane size, blood, exudates, and subretinal fluid. Toxic effects and performance status were graded according to the National Cancer Institute toxicity criteria and Karnofsky performance scale, respectively. Results: Of the 24 treated eyes, 5 (21%) showed objective evidence of anatomic improvement, as defined by decrease in membrane size or improvement in fluorescein angiographic characteristics, but in only 3 of these 5 was the improvement maintained. The same three patients achieved and maintained functional success (visual improvement). Two of the five patients with initial anatomic improvement had subsequent membrane recurrence, which resulted in no visual change in one but visual loss in the other. For the majority of patients, the anatomic and visual status remained the same or became worse after treatment. All patients experienced some degree of adverse reactions involving multiple organ systems. Decreased performance status affected 80% of the patients. Conclusion: This study documents that regression of choroidal neovascularization that occurred with alpha interferon treatment was minimal. Toxic effects interfering with patients' performance status are associated with alpha interferon treatment. Although a randomized trial of interferon versus no therapy may be warranted, fundamental issues (i.e., the biologic properties of interferon versus other more potent agents against choroidal neovascularization, medication dosages, and routes of administration), need to be addressed before embarking on such a trial.