The combination of Interferon and low-dose cyclophosphamide synergistically inhibits the growth of human breast cancer xenografts, explanted human non-small cell lung carcinoma, and other experimental tumors. To determine whether this combination would demonstrate clinical efficacy against refractory solid tumors, we used recombinant alpha-2b-Interferon, 10 MU/m2 subcutaneously three times per week, and cyclophosphamide, 25 mg orally twice daily, in 42 patients (25 renal cell carcinoma, 17 melanoma). Two patients were inevaluable due to premature removal from the study. The toxicity profile did not differ substantially from that of Interferon alone with malaise, fatigue, fevers, and chills predominating. Sixteen percent of patients experienced an alteration in mental status. Of 40 patients evaluable for response, there were two partial responders (one renal cell carcinoma, one melanoma) and four minor responders (all renal cell carcinoma). The responder with melanoma had previously failed therapy with dacarbazine (DTIC). Seventeen patients remained stable for a median follow-up of 6 months. We conclude that this regimen is well tolerated; however, the combination of Interferon and low-dose cyclophosphamide used in this way does not appear to be superior to the same dose and schedule of Interferon used alone.