Staphylococcus aureus meningitis is a challenging disease and little is known about its epidemiology. There are no established management guidelines. We retrospectively reviewed the clinical information, bacteriologic data, and outcomes of all 33 patients with cerebrospinal fluid (CSF) cultures positive for S aureus seen at a single urban teaching hospital from 1999 to 2008. Pulsed-field gel electrophoresis (PFGE) and polymerase chain reaction for staphylococcal cassette chromosome mec (SCCmec), accessory gene regulator (agr) typing, and Panton-Valentine leukocidin (PVL) loci were done on methicillin-resistant S aureus (MRSA) CSF isolates starting in 2005. S aureus caused 12 (36%) cases of postoperative and 21 (64%) cases of hematogenous meningitis. MRSA isolates were found in 6 (50%) cases of postoperative and 10 (48%) cases of hematogenous meningitis. Twelve (75%) of the 16 MRSA infections occurred in the last 5 years of the study. Hematogenous meningitis was associated with older age (p = 0.04), injection drug use (p < 0.01), community-acquired infection (p < 0.01), underlying disease (p = 0.01), staphylococcal infection outside the central nervous system (p = 0.01), altered mental status (p = 0.02), fever (p = 0.01), septic shock (p = 0.03), and bacteremia (p < 0.01). The analysis of the 9 MRSA isolates showed 3 PFGE types: 3 USA100 (33%), 5 USA300 (56%), and 1 USAnot100-1100 (11%). For SCCmec typing, there were 2 (22%) type II and 7 (78%) type IV. All USA300 strains were SCCmec IVa. For agr typing, there were 5 (56%) type I and 4 (44%) type II. Three isolates (33%) were positive for the PVL gene and were USA300 strains. Most patients received nafcillin or vancomycin with or without rifampin or trimethoprim/sulfamethoxazole for a mean period of 17 days (range, 1-42 d). Overall mortality was 36%, and it was associated with community-acquired infection (p = 0.02). Postoperative and hematogenous S aureus meningitis are distinct clinical syndromes. S aureus hematogenous meningitis has devastating clinical consequences and elevated mortality rates, especially if it is acquired in the community. The incidence of MRSA meningitis increased over the last 5 years of the study. Treatment of choice is nafcillin for methicillin-sensitive strains and vancomycin for MRSA strains. The addition of trimethoprim/sulfamethoxazole or rifampin to vancomycin is recommended in severe cases and community-acquired MRSA infections. Linezolid is also a good option due to its good CSF penetration and favorable case reports. The mortality rate is higher in infections acquired in the community.