Necrotic and apoptotic neuronal cell death can be found in pneumococcal meningitis. We have investigated the role of Bcl-2 as an anti-apoptotic gene-product in pneumococcal meningitis using Bcl-2-knockout (Bcl-2 -/-) mice. Using a model of pneumococcal meningitis and cerebritis induced by intracerebral infection, Bcl-2-deficient mice and control littermates were assessed by clinical score and tight rope test (TRT) at 0, 12, 24, 32 and 36h after intracerebral injection of pneumococci (104 CFU/25µl saline) or 25µl normal saline. Then, mice were sacrificed, bacterial titers in blood, spleen and cerebellar homogenates were determined, and the brain and spleen were evaluated histologically. Infected Bcl-2-deficient mice developed more severe clinical illness than infected controls with significant differences in clinical score at 24, 32 and 36h and in TRT at 12 and 32h. Bacterial titers were increased in blood in Bcl-2-deficient mice (mean±SD, 7.46±1.93 logCFU/ml vs. 5.16± 0.96 logCFU/ml, p<0.01). Neuronal damage was most prominent in the hippocampal formation. It did not differ significantly between groups. In-situ-tailing identified only few apoptotic neurons in the brain. The spleen, however, showed significantly more apoptotic leukocytes in Bcl-2-deficient mice than in controls (mean±SD, 5148±3406/mm2 vs. 1070±395/mm2, p<0.005). In uninfected animals there were significantly less apoptotic leukocytes in the spleen. Again, the rate of apoptotic leukocytes in the spleen was higher in Bcl-2-deficient mice than in controls (mean±SD, 118±42 vs. 36±23/mm2, p=0.02). Bcl-2 expression in the spleen of infected control mice after 36 hours determined by Western blot analysis did not differ from uninfected controls. In conclusion, Bcl-2 appears to counteract sepsis-induced apoptosis of splenic lymphocytes thereby enhancing clearance of bacteria from the blood.