To study mechanisms of resistance to Nocardia asteroides in vitro, suspensions of human neutrophils and monocytes were challenged with N. asteroides in the presence of autologous serum. At 4 hr, numbers of viable N. asteroides incubated with neutrophils and monocytes averaged only 10% and 21% less, respectively, than numbers of N. asteroides incubated without phagocytes. In contrast, a mean of > 90% of Listeria monocytogenes and Staphylococcus aureus incubated with neutrophils and monocytes was killed. The failure to kill N. asteroides was not associated with absence of an oxidative metabolic burst by the phagocytes, since chemiluminescence occurred when phagocytes encountered N. asteroides and was blocked in preparations of N. asteroides and neutrophils by preincubation of the neutrophils with chlorpromazine. Thus, when cultured in suspension, human neutrophils and monocytes are unable to kill significant numbers of N. asteroides despite the occurrence of an oxidative metabolic burst.