We aimed to evaluate the usefulness of antistaphylococcal penicillin (ASP) or cephazolin-based combinations versus monotherapy in patients with native-valve infective endocarditis (IE) caused by methicillin-susceptible Staphylococcus aureus (MSSA).Post-hoc analysis of a multicentre prospective cohort. We include patients from 2008 to 2022 with definite native-valve, left-side IE due to MSSA treated primarily with ASP/cephazolin. Patients were categorized according to whether they initially received monotherapy or combination therapy for more than 72 h. A propensity score-matched cohort was planned.Out of 420 included cases, 94 (22.4%) received monotherapy and 326 (77.6%) combination. Median combination duration was 14 days (interquartile range 10-20). Sixty-eight combination cases were matched with 68 monotherapy controls. Baseline characteristics were well balanced. There were no differences in in-hospital or one-year mortality between groups (OR 0.85, 95%CI 0.33-2.18 and HR 0.68, 95%CI 0.35-1.31, respectively). Endocarditis relapses and persistent bacteraemia rates were similar (0% vs 1.5%, p = 1.000; and 19.1% vs 13.2%, p = 0.352, respectively). Drug-related adverse events were more frequent in the combination group (15.0% vs 1.1%, p < 0.001).Antibiotic combinations for patients with native valve left-sided MSSA endocarditis did not improve patient's outcomes. Drug-related adverse events were more frequent in combination patients.