The objective of this retrospective study was to compare the rates of treatment failure, which was a composite of clinical and microbiologic failure, of patients receiving vancomycin and a β-lactam to those receiving vancomycin only for methicillin-resistant (MRSA) bacteremia. Patients 16 to 89 years of age with MRSA bacteremia admitted to a university-affiliated hospital from 1 January 2014 to 31 December 2016 were screened for study inclusion. Patients were eligible if they received>48 h of vancomycin and a β-lactam (combination group) or vancomycin only (standard group) within 48 h after bacteremia onset. A total of 182 patients were screened: 47 were included in the standard group, and 63 were in the combination group. The combination group had a higher baseline body mass index (29.2 ± 8.0 kg/m versus 25.8 ± 7.1 kg/m, = 0.022), acute physiologic assessment and chronic health evaluation-II (APACHE-II) score (median [interquartile range], 21 [15 to 26] versus 16 [10 to 22], = 0.003), and incidence of septic shock (31.8% versus 14.9%, = 0.047). Using multivariate analysis, combination therapy was the only variable that decreased treatment failures (odds ratio [95% confidence interval], 0.337 [0.142 to 0.997]), while vancomycin MIC> 1 mg/liter and male gender increased treatment failures (4.018 [1.297 to 12.444] and 2.971 [1.040 to 8.488], respectively). The 30-day mortality rates (15.0% versus 14.9%, = 1.000) and the incidence of adverse drug events (19.1% versus 23.4%, = 0.816) were not statistically different between the combination and standard groups. Combination therapy of vancomycin with a β-lactam led to significantly fewer treatment failures than vancomycin monotherapy for MRSA bacteremia.