Purpose <p>The optimal treatment for infections due to <i>Stenotrophomonas maltophilia</i> has not been defined.</p> Methods <p>This was a multicenter, retrospective study of patients with <i>S. maltophilia</i> bacteremia between March 2010 to December 2023. Patients &gt; 18 years with a positive blood culture growing <i>S. maltophilia</i> were included. Patients treated &lt; 48&#xa0;h or those with central line colonization were excluded. Clinical failure was defined as emergence of resistance during treatment, recurrent <i>S. maltophilia</i> bacteremia or death within 30 days. Outcomes for those treated with fluoroquinolone or trimethoprim-sulfamethoxazole monotherapy were compared using a propensity scored-adjusted full matching approach.</p> Results <p>217 patients were included; 17% (37/217) patients had a history of transplant. The clinical failure rate was 16% (35/217); reasons for failure included death (<i>n</i> = 22), recurrent bacteremia (<i>n</i> = 12) or treatment-emergent resistance (<i>n</i> = 3). One patient each with recurrence and resistance also died within 30 days. Within 90 days, resistance developed in 15 patients. The most common treatment regimens were fluoroquinolones (<i>n</i> = 103) and trimethoprim-sulfamethoxazole (<i>n</i> = 45) as monotherapy. Use of high-dose trimethoprim-sulfamethoxazole did not improve clinical success rates. Combination therapy was employed in 10% (21/217) of patients. After applying full-matching criteria, there was no difference in rates of 30-day clinical failure (aOR = 1.02; 95% CI 0.25–3.82; <i>P</i> = 0.999) or mortality (aOR = 1.4; 95% CI 0.25–7.25; <i>P</i> = 0.727) among patients treated with fluroquinolone or trimethoprim-sulfamethoxazole monotherapy.</p> Conclusion <p>Monotherapy with fluoroquinolones or trimethoprim-sulfamethoxazole were used most commonly to treat <i>S. maltophilia</i> bacteremia across centers. Patient outcomes did not differ between treatment regimens and the overall rate of treatment-emergent resistance was low.</p>