The clinical course of 60 patients with multiple myeloma was examined for risk factors associated with infection. The overall incidence of infection was 1.46 per patient-year. The greatest risk period for the occurrence of infection was the first two months after the start of initial chemotherapy. The incidence of infection during this period was 4.68 infections per patient-year compared with 1.04 infections per patient-year for subsequent months. Serum creatinine levels of 2 mg/dl or more (p < 0.03) and decreased polyclonal serum immunoglobulins (p < 0.01) predicted increased risk of early infections. Patients infected during the first two months of initial chemotherapy had the same rate of infection during the subsequent clinical course as did patients free of infection during the early treatment period. Thus, the early risk period does not represent only the attrition of susceptible patients. Patients who achieved an objective response had a decrease in infection risk during the time of the response (0.44 infections per patient-year). While response to chemotherapy prolongs life in multiple myeloma, the initiation of chemotherapy is associated with a definable risk period for infections.