Bacterial penetration across the blood-brain barrier (BBB) into the central nervous system is the first step in development of meningitis. The role of tumor necrosis factor-alpha (TNF-alpha) in the penetration process was examined with peripheral infection of Streptococcus pneumoniae type 6. After intraperitoneal infection of S. pneumoniae type 6, the BBB opening was increased continuously from 6 h and the mice died of septic shock within 36 h due to bacterial overgrowth. The bacteria crossed the BBB and began to deposit in brain at 6 h post infection. There was strong staining of TNF-alpha on blood vessels of brain from 6 h to 24 h post infection. Anti-TNF-alpha antibody blocked both the BBB opening and the entrance of circulatory S. pneumoniae type 6 into brain, indicating that TNF-alpha played an important role in controlling the opening of BBB. Furthermore, an adult murine model of hematogenous pneumococcal meningitis was developed that is based on opening of the BBB by TNF-alpha and controlling the degree of bacteremia by cefazolin antibiotic. In conclusion, hematogenous meningitis developed as TNF-alpha initiated BBB opening, peripheral bacteria entered into the brain and formed bacterial emboli, and then progressed to meningitis.