We conducted a retrospective case study at 2 tertiary care centers to determine the clinical implications of trimethoprim-sulfamethoxazole resistant Stenotrophomonas maltophilia (TSRSM). Of 69 reviewed cases (mean age, 57 y; male gender, 70%), 40 (58%) were classified as infections associated with TSRSM (respiratory tract, 14; soft tissue, 11; bloodstream, 8; other sites, 7). Severe underlying comorbidities (86%) and previous antibiotic exposure (99%) were common. Cefotetan (susceptibility, 55%), chloramphenicol (49%) and ticarcillin-clavulanate (45%) showed the highest in vitro activity against TSRSM, but were seldom used for therapy (7%). Among the 40 infected cases, 8 developed sepsis disorders and 8 died. Only 1 death could be directly attributed to autopsy-proven TSRSM infection (pneumonia). McCabe score (p = 0.03) and organ dysfunction (p = 0.006) were associated with an increased risk of death in infected patients; exposure to appropriate therapy tended to be protective against death (p = 0.08). 22 infected patients were treated medically; an additional procedure was necessary to clear the infection in 18 cases (surgery, 13; catheter removal, 5). Isolation precautions were rarely exercised, even in the presence of panresistant isolates. In summary, TSRSM-related infections occurred in severely ill patients with extensive exposure to the health-care system, and often required invasive procedures for cure. Infections were directly associated with severe morbidity, and tended to have an indirect rather than a direct impact on mortality.