We defined the antitumor activity, toxicity, and tolerability of a combined chemoimmunotherapy approach in patients with advanced malignant mesothelioma using daily low-dose interferon alpha-2a and carboplatin given every 4 weeks. This was a phase II study of 15 patients with surgically unresectable or metastatic malignant mesothelioma. All patients had measurable or assessable disease. No prior chemotherapy or immunotherapy was allowable. Carboplatin was given at 150 mg/m2 daily on days 1-3 and interferon alpha-2a at 3 million units subcutaneously daily throughout the study. Treatment was recycled every 28 days. Therapy was continued until disease progression. Fifteen patients were assessable for toxicity and 14 for response. One partial response (7%, 95% CI, 0-20%), with a response duration of 40 weeks, was seen. Most patients had early progression of disease. Toxicity was tolerable, and grade III/IV toxicity was uncommon. The median time to progression was 14 weeks (range, 1-52 weeks). The median survival was 25 weeks (range, 8-66 weeks). The combination of low-dose interferon alpha-2a and carboplatin did not result in greater antitumor activity than that reported for single-agent carboplatin in advanced malignant mesothelioma. Although toxicity was mild, carboplatin and low-dose interferon, given at this dose and schedule, cannot be recommended for this patient group.