We have reported previously that expression of a human CRP transgene (tg) protects mice from lethal 5. pneumoniae infection. In the present study we investigated the role of complement in CRP-mediated protection. Hypocomplementemia was induced in CRP-tg+ and CRP-tg" male mice by injecting i.p. 30 Hg cobra venom factor (CoVF). This treatment resulted in reduction of serum C3 to less than 3% of the normal concentration within 4 h and this effect persisted for 96 h. Four hours after administration of CoVF, S. pneumoniae type 3 (100 CPU) were injected i.p. Bacteremia was determined 24 h after infection and deaths were recorded daily for 10 days. The presence of the CRP tg significantly reduced bacteremia in both normocomplementemic and hypocomplementemic mice (15 mice per group). However, the tg resulted in significantly longer survival time and lower mortality only in the presence of normal complement. On the other hand, the presence of an intact complement system significantly reduced bacteremia and extended survival time, in both CRP-tg+ and CRP-tg" mice, but lowered mortality only in CRP-tg+ mice. We conclude that full expression of the CRP protective effect against S. pneumoniae in CRP-tg + mice requires a functional complement system.