The role of gamma interferon (IFN-gamma) in host defense to Pneumocystis carinii was investigated by use of three different murine models of infection. C57BL/6 scid/scid (severe combined immunodeficient [SCID]) mice were given intratracheal inoculations of P. carinii and reconstituted with splenocytes from either mice with disrupted IFN-gamma genes (IFN-gamma-/- mice) or homozygous wild-type (IFN-gamma+/+) mice. Unreconstituted SCID mice had log10 7.08 +/- 0.13 P. carinii nuclei in their lungs at day 22 postinfection, whereas SCID mice reconstituted with splenocytes from either wild-type or IFN-gamma-/- mice had cleared the infection. However, there was a prolonged and exacerbated inflammatory response in the lungs of SCID mice reconstituted with IFN-gamma-/- splenocytes which was characterized by interstitial pneumonia, eosinophilia, and multinucleated giant cell formation. Similar results were found in C.B17 SCID mice reconstituted with CD4+ cells from P. carinii-immunized donors treated with neutralizing anti-IFN-gamma monoclonal antibody (MAb). These mice resolved their P. carinii infections; however, they also exhibited exacerbated lung pathology compared with mice treated with a control MAb. Finally, IFN-gamma-/- mice challenged intratracheally with P. carinii resolved their infection within 56 days as did IFN-gamma+/- mice. Furthermore, depletion of T cells in vivo with a MAb resulted in IFN-gamma-/- mice becoming susceptible to P. carinii infection. Together, these data indicate that IFN-gamma is not required for resolution of P. carinii infection; however, in the absence of IFN-gamma, there is a prolonged and exacerbated P. carinii-driven interstitial pneumonia characterized by eosinophilia and formation of multinucleated giant cells.