Despite the increasing incidence of vancomycin-intermediate Staphylococcus aureus (VISA) infections, few studies have examined the impact of delay in receipt of appropriate antimicrobial therapy on outcomes in VISA patients. We examined the effects of timing of appropriate antimicrobial therapy in a cohort of patients with sterile-site methicillin-resistant S. aureus (MRSA) and VISA infections. In this single-center, retrospective cohort study, we identified all patients with MRSA or VISA sterile-site infections from June 2009 to February 2015. Clinical outcomes were compared according to MRSA/VISA classification, demographics, comorbidities, and antimicrobial treatment. Thirty-day all-cause mortality was modeled with Kaplan-Meier curves. Multivariate logistic regression analysis (MVLRA) was used to determine odds ratios for mortality. We identified 354 patients with MRSA (n = 267) or VISA (n = 87) sterile-site infection. Fifty-five patients (15.5%) were nonsurvivors. Factors associated with mortality in MVLRA included pneumonia, unknown source of infection, acute physiology and chronic health evaluation (APACHE) II score, solid-organ malignancy, and admission from skilled care facilities. Time to appropriate antimicrobial therapy was not significantly associated with outcome. Presence of a VISA infection compared to that of a non-VISA S. aureus infection did not result in excess mortality. Linezolid use was a risk for mortality in patients with APACHE II scores of ≥14. Our results suggest that empirical vancomycin use in patients with VISA infections does not result in excess mortality. Future studies should (i) include larger numbers of patients with VISA infections to confirm the findings presented here and (ii) determine the optimal antibiotic therapy for critically ill patients with MRSA and VISA infections.