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Background: The aim of this study was to compare the safety and effectiveness of monotherapy versus combination therapy for the treatment of infections caused by S. maltophilia. Methods: This retrospective, multicenter, cohort study included patients treated with either monotherapy or combination therapy for infections caused by S. maltophilia. Primary outcomes included overall in-hospital mortality, 30-day mortality, and clinical cure. Safety outcomes were also evaluated. Multivariable logistic regression was used as a control for confounding variables. Results: A total of 407 patients were included, 330 patients received monotherapy and 77 patients received combination therapy. A total of 21% presented with concomitant bacteremia. After adjusting the differences between the two groups, there were no statistically significant differences between patients who received monotherapy versus combination therapy in clinical cure (55% vs 65%; OR, 0.72; 95% CI, 0.40–1.31) and overall in-hospital mortality (52% vs 49%; OR, 0.84; 95% CI, 0.45–1.57). However, patients who received monotherapy had a lower rate of 30-day mortality (28% vs 32%; OR, 0.45; 95% CI, 0.22–0.90) and acute kidney injury (9% vs 18%; OR, 0.35; 95% CI, 0.16–0.78). Conclusion: Clinical outcomes did not significantly differ in patients who received combination therapy versus monotherapy. More data are needed to validate these findings. [ABSTRACT FROM AUTHOR]