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Stenotrophomonas maltophilia is an opportunistic pathogen primarily associated with hospital-acquired infections, particularly in individuals who are immunocompromised. S. maltophilia infections pose a significant clinical challenge due to the bacterium's sophisticated intrinsic and acquired mechanisms, which render it naturally multidrug resistant. The management of such infections is thus difficult, as the availability of effective therapeutic agents is limited. Antibiotic therapy options include co-trimoxazole, minocycline, tigecycline, levofloxacin, cefiderocol, and ceftazidime-avibactam. Co-trimoxazole, which comprises a synergistic combination of trimethoprim and sulfamethoxazole, remains the recommended first-line therapy for S. maltophilia infections. In this review, we critically evaluate the current evidence on the efficacy of co-trimoxazole against S. maltophilia. The present global prevalence of co-trimoxazole resistance in S. maltophilia clinical isolates varies from <5% to approximately 44%, raising concerns about its long-term reliability. Resistance to co-trimoxazole arises through several mechanisms. Horizontal gene transfer can introduce sul genes, which encode sulfonamide-insensitive dihydropteroate synthase, or dfrA genes, which encode trimethoprim-insensitive dihydrofolate reductase. Both enzymes function within the folate biosynthesis pathway, and their expression directly confers co-trimoxazole resistance. S. maltophilia can also acquire co-trimoxazole resistance through genetic mutations. The overexpression of efflux systems such as SmeVWX and SmeDEF, contributes to high-level resistance to co-trimoxazole, often triggered by mutations in the transcriptional regulators. Resistant strains frequently emerge due to improper antimicrobial use, as environmental antibiotic residues can act as selection pressure, facilitating the emergence and persistence of resistant strains. Despite these challenges, co-trimoxazole continues to demonstrate substantial clinical utility. It remains effective in many settings, either as monotherapy or in combination with other antibiotics such as minocycline, tigecycline, cefiderocol, or levofloxacin, and often achieves favorable outcomes.