The effects of exchange transfusion with Fluosol DA (FDA) or stroma-free hemoglobin on the outcome of pneumococcal infection in rats were determined. Rats were sham transfused or exchange transfused with 25 ml of FDA or stroma-free hemoglobin. They were then challenged intraperitoneally with Streptococcus pneumoniae type 3 and treated with penicillin for 120 h. Only 2 of 15 (13.3%) FDA-transfused rats were alive at 312 h compared with 11 of 15 (73.3%) concurrently studied sham-transfused control rats (P = 0.0016). Of 10 stroma-free hemoglobin-transfused rats and 10 concurrently studied sham-transfused control rats (P = 0.98), 8 from each group (80%) were alive at 312 h. Penicillin therapy only suppressed pneumococcal infection in FDA-transfused rats, and relapse occurred after therapy was stopped. This effect could not be attributed to interference with the bactericidal activity of penicillin against pneumococci, to an alteration in the pneumococcal burden before penicillin therapy or to an alteration of the leukocyte and polymorphonuclear leukocyte response by FDA. In contrast, pneumococcal infection in stroma-free hemoglobin-transfused rats was cured with penicillin therapy. These data showed that FDA altered the ability of rats to respond to pneumococcal infection.