Background: Cathodic voltage-controlled electrical stimulation (CVCES) of titanium implants, either alone or combined with a short course of vancomycin, has previously been shown to reduce the bone and implant bacterial burden in a rodent model of methicillin-resistant Staphylococcus aureus (MRSA) implant-associated infection (IAI). Clinically, the goal is to achieve complete eradication of the IAI; therefore, the rationale for the present study was to evaluate the antimicrobial effects of combining CVCES with prolonged antibiotic therapy with the goal of decreasing the colony-forming units (CFUs) to undetectable levels. Questions/purposes: (1) In an animal MRSA IAI model, does combining CVCES with prolonged vancomycin therapy decrease bacteria burden on the implant and surrounding bone to undetectable levels? (2) When used with prolonged vancomycin therapy, are two CVCES treatments more effective than one? (3) What are the longer term histologic effects (inflammation and granulation tissue) of CVCES on the surrounding tissue? Methods: Twenty adult male Long-Evans rats with surgically placed shoulder titanium implants were infected with a clinical strain of MRSA (NRS70). One week after infection, the rats were randomly divided into four groups of five: (1) VANCO: only vancomycin treatment (150 mg/kg, subcutaneous, twice daily for 5 weeks); (2) VANCO + 1STIM: vancomycin treatment (same as the VANCO group) coupled with one CVCES treatment (−1.8 V for 1 hour on postoperative day [POD] 7); (3) VANCO + 2STIM: vancomycin treatment (same as the VANCO group) coupled with two CVCES treatments (−1.8 V for 1 hour on POD 7 and POD 21); or (4) CONT: no treatment. On POD 42, the implant, bone, and peripheral blood were collected for CFU enumeration and histological analysis, where we compared CFU/mL on the implants and bone among the groups. A pathologist, blinded to the experimental conditions, performed a semiquantitative analysis of inflammation and granulation tissue present in serial sections of the humeral head for animals in each experimental group. Results: The VANCO + 1STIM decreased the implant bacterial burden (median = 0, range = 0–10 CFU/mL) when compared with CONT (median = 5.7 × 10 4 , range = 4.0 × 10 3 −8.0 × 10 5 CFU/mL; difference of medians = −5.6 × 10 4 ; p < 0.001) and VANCO (median = 4.9 × 10 3 , range = 9.0 × 10 2 −2.1 × 10 4 CFU/mL; difference of medians = −4.9 × 10 3 ; p < 0.001). The VANCO + 1STIM decreased the bone bacterial burden (median = 0, range = 0–0 CFU/mL) when compared with CONT (median = 1.3 × 10 2 , range = 0–9.4 × 10 2 CFU/mL; difference of medians = −1.3 × 10 2 ; p < 0.001) but was not different from VANCO (median = 0, range = 0–1.3 × 10 2 CFU/mL; difference of medians = 0; p = 0.210). The VANCO + 2STIM group had implant CFU (median = 0, range = 0–8.0 × 10 1 CFU/mL) and bone CFU (median = 0, range = 0–2.0 × 10 1 CFU/mL) that were not different from the VANCO + 1STIM treatment group implant CFU (median = 0, range = 0–10 CFU/mL; difference of medians = 0; p = 0.334) and bone CFU (median = 0, range = 0–0 CFU/mL; difference of medians = 0; p = 0.473). The histological analysis showed no deleterious effects on the surrounding tissue as a result of the treatments. Conclusions: Using CVCES in combination with prolonged vancomycin resulted in decreased MRSA bacterial burden, and it may be beneficial in treating biofilm-related implant infections. Clinical Relevance: CVCES combined with clinically relevant lengths of vancomycin therapy may be a treatment option for IAI and allow for component retention in certain clinical scenarios. However, more animal research and human trials confirming the efficacy of this approach are needed before such a clinical recommendation could be made.