PurposeStenotrophomonas maltophiliais a Gram-negative pathogen that most commonly causes hospital-acquired infections that can be extremely challenging to treat, contributing to underrecognized mortality throughout the world. The relative benefits of monotherapy as compared to combination therapy in patients diagnosed withS. maltophiliapneumonia, however, have yet to be established.MethodsData from 307 patients diagnosed withS. maltophiliahospital-acquired pneumonia (HAP) across four Chinese teaching hospitals from 2016 to 2022 were retrospectively analyzed.ResultsOf the analyzed patients, 55.7% (171/307) were administered combination definitive therapy, with a 30-day all-cause mortality rate of 41.0% (126/307). A propensity score weighting analysis revealed that compared with monotherapy, combination definitive therapy was associated with a comparable 30-day mortality risk in the overall patient cohort (OR1.124, 95% CI0.707–1.786, P= 0.622), immunocompetent patients (OR1.349, 95% CI0.712–2.554, P= 0.359), and patients with APACHE II scores < 15 (OR2.357, 95% CI0.820–6.677, P= 0.111), whereas it was associated with a decreased risk of death in immunocompromised patients (OR0.404, 95% CI.170–0.962, P= 0.041) and individuals with APACHE II scores ≥ 15 (OR0.494, 95% CI0.256–0.951, P= 0.035).ConclusionThe present data suggest that when treatingS. maltophilia-HAP, immunocompromised patients and individuals with APACHE II scores ≥ 15 may potentially benefit from combination therapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13613-023-01144-7.