Sublethal irradiation of BALB/c mice 4 hours prior to inoculation with 5 X 10(4) virulent Brucella abortus, caused significant (P < 0.01) reductions in bacterial numbers in comparison with numbers in unirradiated controls. Numbers of brucellae in the spleen were significantly lower by 5 days after inoculation and decreased thereafter, so that at 2 and 3 weeks after inoculation, there were up to 1,000-fold fewer organisms in the spleen of irradiated mice. The number of brucellae in the spleen increased in irradiated mice thereafter. The course of events in the liver was similar, but developed more slowly, and peak differences in bacterial numbers were about 1 log less. These phenomena were not attributable to differences in implantation of brucellae in the liver or spleen, nor to an abnormal distribution of organisms in other organs of irradiated mice. Irradiation of mice during the plateau phase of infection also resulted in significant (P < 0.05) reductions in bacterial counts in the spleen during the succeeding 4 weeks. Macrophage activation in the spleen, measured by a Listeria monocytogenes-killing assay, was significantly (P < 0.01) increased by irradiation alone at 1 week after inoculation and at that time was significantly (P < 0.01) greater in B abortus-infected, irradiated mice than in B abortus-infected controls. Histologic, cytologic, and immunologic studies revealed that the decrease in numbers of organisms between 1 and 2 weeks after inoculation in irradiated mice occurred at a time when their immune response to B abortus was suppressed and when numbers of neutrophils and monocytes infiltrating the spleen were significantly (P < 0.01) diminished. The increase in numbers of B abortus in organs of irradiated mice that began after the third week coincided with recovery of the immune response and an increase in numbers of neutrophils and monocytes in the infected organs. The course of B abortus infection was not substantially altered during the first 11 days after inoculation in mice infected at the height of a profound monocytopenia and neutropenia induced by azathioprine, a drug that by itself failed to activate macrophages. We hypothesized that, in irradiated mice, a rapid radiation-induced activation of resident macrophages to a brucellacidal state was coupled with an absence of newly formed monocytes in which virulent strains of B abortus could establish persistent infection, and that as susceptible monocytes emerged in mice recovering from the effects of irradiation, chronic infection became established.