This study focuses on the effect of TEPC-183 (tetramethylpentadecane)-induced plasmacytoma on resistance of mice to infection with Streptococcus pneumoniae type III. Vaccination of normal or of TEPC-183-bearing mice with either a polyvalent pneumococcal vaccine (Pnu-Imune) or purified polysaccharide type III protects both against challenge with live S. pneumoniae. However, a 38-fold increase in susceptibility of the tumor-bearing mice over that of controls was observed. Immunized splenectomized mice were ten times more susceptible to infection than were immunized normal mice. However, this increased susceptibility of splenectomized mice could be overcome by passively administered antibody. In passive protection experiments, antisera obtained from normal and TEPC-183-bearing or from cyclophosphamide-treated mice were almost equally protective. A 6-fold increase of antibody (133 ng of antibody), however, was required to protect TEPC-183-bearing mice against challenge with 500 organisms, as compared with the 22 ng of antibody required to protect normal mice, indicative of defective host defense mechanisms in addition to the lower production of antibody in the TEPC-183-bearing mice. In contrast, mice bearing an equal tumor load of Sarcoma 37 behaved similarly to normal mice, showing that the increased susceptibility to infection was due to TEPC-183, a particularly immunosuppressive tumor.