BACKGROUND The purpose of this study was to determine whether preoperative skin preparation with hydrogen peroxide reduces intraoperative culture positivity for Cutibacterium acnes in shoulder arthroplasty. METHODS This was a prospective, controlled, parallel/noncrossover, nonrandomized, single-blinded trial registered at clinicaltrials.gov. We included a consecutive series of patients scheduled to undergo primary anatomic or reverse total shoulder arthroplasty. The first group of patients underwent a standard skin preparation and the second group underwent the same preparation with the addition of hydrogen peroxide. We then took skin, dermis, glenohumeral joint, and air (negative control) aerobic and anaerobic culture swabs. We blinded the laboratory analyzing the samples. An a priori power analysis determined that 56 patients would be needed to see a 50% reduction in culture positivity rates. We also conducted a post hoc gender-stratified analysis. RESULTS Between January 2017 and October 2018, the authors performed 124 primary shoulder arthroplasties, of which we included 65 and collected samples on 61. There were no demographic differences. There were fewer patients within the peroxide group with triple-positive cultures (skin, dermis, and joint) (0% vs. 19%, P = .024) and positive cultures from the joint (10% vs. 35%, P = .031). In our subgroup analysis, these differences were only significant in males. The vast majority of positive cultures were with C. acnes. CONCLUSIONS Although larger, randomized studies are needed, adding hydrogen peroxide to the preoperative skin preparation may be a low-cost, low-risk method to reduce deep tissue contamination with C. acnes, particularly within males.