Stenotrophomonas maltophilia is an opportunistic, gram-negative bacillus with few therapeutic options due to a high level of intrinsic resistance. Trimethoprim/sulfamethoxazole (SXT) is recommended as the first-line treatment; however, minocycline (MIN) has been shown to have similar clinical outcomes in treating S. maltophilia and addresses concern for increasing resistance to SXT. The objective of this study is to evaluate the efficacy and safety outcomes of nonurinary, monomicrobial infections due to S. maltophilia in hospitalized patients treated with MIN or SXT. This was a retrospective study of hospitalized adult patients receiving MIN or SXT for nonurinary monomicrobial S. maltophilia infection from April 1, 2018 to March 31, 2020. The primary outcome was clinical disposition classified as rates of clinical failure, clinical improvement, or clinical success. Eighty-two patients (88.2%) received MIN and 11 patients (11.8%) received SXT initially. Clinical failure occurred in 16 (19.5%) patients in the MIN group and in 4 (36.4%) patients in the SXT group (P = 0.242). Clinical improvement occurred in 11 (13.4%) patients in the MIN group and in 1 (9.1%) patient in the SXT group (P = 1.0). Clinical success occurred in 55 (67.1%) patients in the MIN group and in 6 (54.5%) patients in the SXT group (P = 0.503). Total duration of antimicrobial therapy (P = 0.3198), in-hospital mortality (P = 1.0), hospital length of stay (P = 0.9668), intensive care unit (ICU) length of stay (P = 0.1384), and 30-day readmission (P = 0.686) were similar between groups. Rates of clinical failure, clinical improvement, or clinical success were similar between MIN and SXT for nonurinary monomicrobial S. maltophilia infections.