ABSTRACT 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.