Purpose. The impact of an institutional protocol intended to improve daptomycin dosing for vancomycin-resistant enterococci (VRE) infections was investigated. Summary. Daptomycin has been reported to have optimal activity against VRE at weight-based doses of ≥8 mg/kg. As part of an initiative to optimize daptomycin dosing for all indications and regimens, a large medical center implemented a protocol restricting daptomycin prescribing to infectious-diseases specialists and a nomogram recommending elevated daptomycin dosing for all VRE infections, with baseline and weekly creatinine phosphokinase (CPK) determinations during daptomycin therapy. Protocol implementation was preceded by educational efforts targeting medical and pharmacy staff. A retrospective study was conducted to compare prescribing behavior and safety monitoring rates during the 12 months before and 16 months after protocol implementation; the baseline characteristics of the preimplementation cohort (n = 95) and postimplementation cohort (n = 72) were similar. The mean daptomycin doses before and after the protocol was implemented were 453 mg (6.1 mg/kg) and 576 mg (7.6 mg/kg), respectively. After protocol implementation, there were significant increases in the proportion of patients who received doses of ≥8 mg/kg (52% in the postimplementation period versus 4% in the preimplementation period, p < 0.05) and in the rate of baseline CPK assessment (64% versus 43%, p < 0.05). Conclusion. Implementation of a daptomycin dosing protocol by a multidisciplinary antimicrobial stewardship team optimized treatment by increasing the mean dose of daptomycin administered to hospitalized adults with non-urinary VRE infections and improved the rate of safety monitoring.