Mouse peritoneal and alveolar macrophages differed substantially in their response to influenza in vitro. Immunofluorescent and infectious-center techniques showed that viral proteins were produced in only a small subpopulation (17%) of peritoneal macrophages and that these infected cells were removed from culture by 3 days postinfection. In contrast, alveolar macrophages were highly susceptible to influenza, and viral antigens were produced in all cells. This was accompanied by a cytopathic effect and cell death. However, no infectious virus was released and the infection was considered abortive. With mouse cytomegalovirus, however, both alveolar and peritoneal macrophages were equally restrictive, and viral antigens were produced in only 1 to 5% of either cell population. No significant differences were observed between mouse-virulent and -avirulent strains of influenza in their interaction with macrophages either in vitro or in vivo. In vivo, both strains induced an influx of cells to the alveolar spaces by 3 to 4 days postinfection, and this was reflected by a 5- to 10-fold increase in the number of "macrophages" in harvest fluids at this time. Many of these cells had an altered morphology compared with alveolar macrophages from uninfected mice, and the cell population as a whole was not susceptible to influenza. However, this resistance was lost by 7 days of in vitro culture.