Stenotrophomonas (Xanthomonas) maltophilia is a rare cause of endocarditis. The extensive resistance of this organism to several antibiotics leaves few options for antimicrobial therapy. In vitro synergism of the combination of trimethoprim-sulfamethoxazole (TMP-SMZ) and ticarcillin/clavulanic acid (TIC/CA) has been demonstrated. To our knowledge, we report the first case of ventriculoatrial cerebrospinal fluid shunt-associated endocarditis due to S. maltophilia. The patient was cured with combination therapy with TMP-SMZ and TIC/CA along with catheter removal. This is also the first report of S. maltophilia endocarditis successfully treated with this antibiotic combination. In a review of the medical literature, only 16 cases of S. maltophilia endocarditis were found. Most patients were intravenous drug users (43.8%) or had either prosthetic heart valves (50%) or an indwelling vascular catheter (18.8%). Although S. maltophilia is usually considered a nosocomial pathogen, about one-half of the cases were community-acquired. Twelve of sixteen patients had left-sided endocarditis. Therapy with a combination of two or more antibiotics was employed in most cases. Seven patients had been given TMP-SMZ therapy, but none had been treated with TIC/CA before. One-half of the patients required cardiac surgery. The overall mortality rate was 33%. Although the optimal antibiotic treatment for S. maltophilia endocarditis remains unknown, the case reported herein reinforces in vitro findings that the combination of TMP-SMZ and TIC/CA may be effective therapy.