The interaction of Nocardia asteroides with cultured "normal" nonimmune rabbit alveolar macrophages was studied by light and electron microscopy. It was shown that the alveolar macrophage response to the more virulent strain (N. asteroides 14759) was quite different from the response to the less virulent organism (N. asteroides 10905). N. asteroides 14759 elicited a dramatic in vitro response of the macrophages toward the nocardial infection. Within a few hours postinfection, there was a migration of macrophages toward other cells actively infected with viable nocardia, so that at 6 h considerable macrophage aggregation on the cover slips had occurred. Many of the macrophages within these aggregates exhibited tight cell-to-cell contact, whereas others were observed to fuse, forming multinucleate giant cells, with many containing more than 10 nuclei. Upon continued incubation, these giant cells appeared to destroy the intracellular nocardia, so that, at 24 h postinfection, gram-positive, ultrastructurally intact bacteria could not be observed. At the same time, some of the macrophage aggregates that did not fuse appeared to be unable to stop the intracellular growth of nocardia. At 12 to 24 h large numbers of gram-positive, acid-fast filaments were observed growing out from within these macrophage aggregates. The macrophage response seemed dependent upon the strain of Nocardia infecting them, since N. asteroides 10905 did not induce a similar response within the macrophage population.