Immune protection from endocarditis caused by Streptococcus defectivus was examined by using a rabbit model. Previously we had demonstrated that immunization with nutritionally variant streptococci (NVS, now referred to as Streptococcus, species defectivus and adjacens) protected rabbits against endocarditis when they were challenged with the homologous strain. However, when high-titer immune globulin was transferred to nonimmunized rabbits, no protection was achieved. In the present study, immunosuppressive treatments were given to previously immunized rabbits, and alterations in the level of protection were determined by using the rabbit endocarditis model. Control-immunized rabbits as well as immunized rabbits receiving cyclosporin A or methylprednisolone treatments were protected from S. defectivus endocarditis at levels between 50% and 67%. Rabbits in each of these groups cleared S. defectivus organisms from the circulation by 3 hours after infection. Nitrogen mustard-treated rabbits (immunized or nonimmunized), however, were unable to clear S. defectivus organisms as efficiently (almost 100 times as many organisms in the blood when compared with other groups) by 3 hours, and all were susceptible to endocarditis. These data suggest that circulating phagocytes such as monocytes and granulocytes function to a certain extent in protection against S. defectivus endocarditis. Moreover, when neutrophils were transfused into granulocytopenic and monocytopenic rabbits, efficient clearance was prolonged, indicating that polymorphonuclear leukocytes were involved in the later (greater than 1 hour after infection) phase of protection.