Trimethoprim-sulfamethoxazole (TMP-SMZ) is recommended as the treatment of choice for Stenotrophomonas maltophilia infections. However, when the administration of TMP-SMZ is not possible, alternative treatment options for S. maltophilia infections has not been clearly established. We compare the efficacy of tigecycline treatment with TMP-SMZ in nosocomial S. maltophilia infections during a 3-year period. For the treatment of S. maltophilia infection, 26 (57.8%) patients received TMP-SMZ and 19 (42.2%) patients received tigecycline. Culture positivity rate was 95.7% in TMP-SMZ group and 70.6% in tigecycline group at the seventh day (P = 0.028), whereas 26.3% versus 18.8% at the fourteenth day (P = 0.700). Clinical improvement was observed 69.2% in TMP-SMZ group and 68.4% in tigecycline group at the fourteenth day (P = 0.954). Mortality rates at the thirtieth day were respectively, 30.8 and 21.1% in TMP-SMZ and tigecycline groups (P = 0.517). There were no significant differences in mortality and clinical response rates between TMP-SMZ and tigecycline treatment. Tigecycline can be considered as an alternative option beyond TMP-SMZ in treatment of S. maltophilia infections.