Introduction Current guidelines recommend maintaining vancomycin trough concentrations between 15–20 mg/L for serious methicillin resistant staphylococcus aureus (MRSA) infections. This recommendation is based on limited evidence. Methods A retrospective study including patients with vancomycin susceptible MRSA infections (MIC< = 2 mg/L), treated with vancomycin. We compared outcomes among patients attaining high (> = 15mg/L) vs low (<15mg/L) trough vancomycin levels. We used a propensity score to matching patients achieving low and high levels and conducted an adjusted analysis in the propensity score (PS)-matched cohort using regression analysis. Primary outcome was 30-day all-cause mortality. Results Among 285 patients included, there were no significant differences between patients achieving high and low vancomycin levels in mortality (46/131, 35.1% vs 41/154, 26.6%), clinical success, microbiological success, or nephrotoxicity. Similarly, in the PS-matched cohort (n = 162), there was no significant difference in mortality between patients with high and low vancomycin levels (24/53, 45.3% vs 57/109, 52.3%, respectively), adjusted odds ratio for mortality with high levels 0.63 (95% confidence interval 0.28–1.43). In both cohorts, patients with pneumonia achieving high levels had significantly higher clinical and microbiological success (PS-matched cohort: clinical success: 16/32, 50.0% vs 5/27, 18.5%, p = 0.012; microbiological success: 19/32, 59.4% vs 7/27, 25.9%, p = 0.010), without significant differences in mortality. Conclusions We found no association between vancomycin levels > = 15 mg/L and clinical outcomes in patients with MRSA infections. In patients with MRSA pneumonia, vancomycin levels > = 15 mg/L were associated with higher clinical success rates. Further larger cohort studies are needed to define optimal vancomycin levels according to the site of infection.