BACKGROUND Cutibacterium acnes (C acnes) colonization can have a significant impact on patients undergoing both arthroscopic and open shoulder surgery with regard to postoperative infection. Its resistance to standard preoperative skin preparations and prophylactic antibiotics has led to a need for a more targeted therapy. Topical benzoyl peroxide (BPO) has been used by dermatologists in the treatment for acnes due to its bactericidal and penetrative effects through the dermal layer. The aim of this systematic review is to review the effectiveness of topical BPO preoperatively in shoulder surgery in reducing C acnes colonization and postoperative infection. METHODS A review of the online databases Medline and Embase was conducted on December 15, 2021, according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The review was registered prospectively in the PROSPERO database. Clinical studies reporting superficial and deep sample microbiology and postoperative complications were included. The studies were appraised using the revised Cochrane Risk of Bias 2 (ROB 2) tool for randomized studies and the Methodological Index for Non-Randomized Studies (MINORS) tool. RESULTS The search strategy identified 10 studies for inclusion (6 randomized control trials, 2 prospective cohort studies, and 2 case series), including a total of 482 patients. Seven studies were comparable, testing BPO against alternative standard skin preparations. Of the 10 studies, 7 showed a decrease in the load of C acnes on the skin and/or deep tissues, of which 6 demonstrated statistical significance. Men were shown to have a statistically significant increase in the colonization rate of C acnes. Scheer et al (2021) demonstrated 4500 colony-forming units/mL in males and 900 colony-forming units/mL in females. In studies where the number of BPO applications was higher, BPO appeared more effective. Dizay et al demonstrated C acnes elimination in 78.9% with more than 1 application compared with 66.7% if only applied once. Three studies looked at the effectiveness of BPO during the operative timeline with 1 demonstrating its statistically significant effectiveness at reducing colonization 2 hours into the operation (P = .048). CONCLUSIONS BPO is effective as a topical treatment at reducing C acnes colonization before shoulder surgery. However, the relationship between duration of treatment, frequency of application, and gender requires further research.