It is well established that Pneumocystis carinii has the molecular capability for variation of a major surface antigen, glycoprotein A(gpA). However, the extent of expression of gpA variation among P. carinii infecting a single host and whether this variation has any impact on host-parasite immunological interactions is unknown. Using a mouse model ofP. carinii pneumonia we were able to demonstrate the expression of more than one gpA phenotype in a closed population of infected mice. Administration of monoclonal antibody 2B5, which is specific for one of the gpA phenotypes, resulted in a marked diminution in the frequency of this particular gpA phenotype in the population of organisms. This effect was due to a loss of trophozoites bearing the specific epitope recognized by the 2B5 mAb; cysts bearing the same epitope appeared unaffected. Interestingly,P. carinii were unable to introduce a new phenotype into the population to compensate for the loss of trophozoites bearing the epitope recognized by the 2B5 mAb. Release of 2B5 mAb pressure allowed the 2B5 mAb-binding phenotype to reemerge. This suggests that the phenotype recognized by 2B5 mAb was continually produced even when 2B5 mAb was present. Thus, although P. carinii exhibited a form of antigenic variation, the inability to rapidly introduce new phenotypes into the population in response to binding by antibodies may help to explain why P. carinii is an opportunistic rather than an overt pathogen.