Stenotrophomonas maltophilia (S. maltophilia) has recently emerged as an important nosocomial pathogen. Treatment of invasive infections caused by this organism is difficult as the bacterium is frequently resistant to a wide range of commonly used antimicrobials. Trimethoprim-sulfamethoxazole (TMP - SXT) is recommended as the agent of choice for the treatment of S. maltophilia infections. However, the development of resistance to this antibiotic represents a real challenge to laboratorians and clinicians. This letter describes the first isolation of S. maltophilia resistant to TMP - SXT from two patients treated at Riyadh Armed Forces Hospital which is a major tertiary hospital in Saudi Arabia.