Objectives The therapeutic arsenal for MRSA infections is limited. The aim of this study was to assess the non-inferiority of a combination of trimethoprim/sulfamethoxazole plus rifampicin versus linezolid alone for the treatment of MRSA infection. Methods We conducted a randomized, open-label, single-centre, non-inferiority trial comparing trimethoprim/sulfamethoxazole (160 mg/800 mg three times daily) plus rifampicin (600 mg once a day) versus linezolid (600 mg twice a day) alone in adult patients with various types of MRSA infection. Patients were allocated 1: 1 to either regimen. The primary outcome was clinical cure at 6 weeks after the end of treatment (non-inferiority margin 20%) assessed by both ITT and PP analyses. Secondary outcomes included the microbiologically documented persistence of MRSA in clinical cultures, mortality and adverse events. The study protocol has been registered with ClinicalTrials.gov (NCT00711854). Results Overall, 150 patients were randomized to one of the two treatment arms between January 2009 and December 2013 and were included in the ITT analysis. Of these 56/75 (74.7%) in the linezolid group and 59/75 (78.7%) in the trimethoprim/sulfamethoxazole and rifampicin group experienced clinical success (risk difference 4%, 95% CI −9.7% to 17.6%). The results were confirmed by the PP analysis, with 54/66 (81.8%) cured patients in the linezolid group versus 52/59 (88.1%) in the trimethoprim/sulfamethoxazole and rifampicin group (risk difference 6.3%, 95% CI −6.8% to 19.2%). There were no statistically significant differences between the two groups in any of the secondary outcomes, including microbiologically documented failure. Four adverse drug reactions attributed to the study medication occurred in the linezolid group versus nine in the trimethoprim/sulfamethoxazole and rifampicin group. Conclusions Compared with linezolid, trimethoprim/sulfamethoxazole and rifampicin seems to be non-inferior in the treatment of MRSA infectio
