Pneumocystis carinii, a leading opportunistic pulmonary pathogen, contains a major surface glycoprotein (MSG) which plays a central role in its interaction with the host. Naive Lewis rats were immunized with varying concentrations of purified native MSG and a recombinant form of the protein (MSG-B), placed in a conventional rat colony with exposure to P. carinii, and immunosuppressed with corticosteroids for 10 weeks to induce the development of pneumocystosis. Immunization elicited humoral and cellular immune responses to MSG which persisted throughout the experiment. Compared with animals immunized with ovalbumin or adjuvant alone, the MSG-immunized rats had improved survival (29 vs 66%, p<0.001), lowered organism burden (log₁₀ 9.03±0.33/lung vs 7.51±0.38/lung, p<0.001), less alveolar involvement as assessed by lung histologic score (3.54±0.42 vs 2.50±0.42, p<0.01) and lung weight:body weight ratio (18.2±1.4 vs 14.6±1.7, p<0.01). Animals immunized with MSG-B also showed a significantly lower organism burden, lung histologic score and lung weight:body weight ratio than control rats. Thus, MSG is the first P. carinii antigen which can elicit a protective response in the immunosuppressed rat model of pneumocystosis and this finding supports the rationale of developing a P. carinii vaccine.