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Background: Previous literature has demonstrated high rates of Cutibacterium acnes (C. acnes) colonization in patients undergoing primary shoulder arthroplasty. Residing primarily within the dermal layer, C. acnes poses a major threat to intraoperative wound contamination with subsequent risk of developing periprosthetic joint infection. Discovering an effective perioperative prophylaxis strategy is imperative. To date, no such regimen has shown the ability to reliably suppress C. acnes from the deeper tissues. This study was designed to investigate whether intraoperative Irrisept irrigation would result in a lower positive culture rate of C. acnes versus standard prophylaxis alone in primary total shoulder arthroplasty., Methods: Patients undergoing primary shoulder arthroplasty were randomized to the standard control group or the experimental Irrisept group. Intraoperative cultures were obtained from the incision site, dermis, inferior glenohumeral recess, and sterile kidney basin (control). All specimens were collected by one surgeon at one institution. Samples were shipped to ACM Global Laboratories. All cultures were observed for 14 days. Statistical analysis of the control and experimental quantitative values were compared via Fisher's exact test. Nominal variables were evaluated using the chi-square test. Multivariate analysis was performed to evaluate for differences in age, body mass index, smoking history, diabetic status, VAS, and ASES scores. Significance for all comparisons was p ≤ 0.05., Results: Final analysis included 56 patients and 223 cultured specimens. Baseline demographics were similar between cohorts, indicating successful randomization. C. acnes positive culture rate of the control group did not significantly differ from the Irrisept group (5.77% versus 10.08%; P=0.49). No differences were noted in subgroup analysis. The total positive culture rate of all specimens was 8.07% (18/223). Incision site cultures had the highest rate of positivity (14.2%), followed by the dermis (7.14%), deep tissue (5.5%), and control (5.4%). No difference in culture rates were detected regarding age, BMI, smoking history, diabetic status, VAS, or ASES scores. There was 98.2% follow-up at two weeks, 91.1% at six weeks, 83.9% at three months, and 71.4% at six months. No additional complications or adverse events were noted in either cohort., Conclusion: The addition of intraoperative Irrisept irrigation did not significantly differ from standard perioperative prophylaxis for C. acnes positive culture rates in patients undergoing primary shoulder arthroplasty. While the findings should be cautiously interpreted due to the limited sample size, this pilot study provides a useful framework to inform a larger randomized controlled trial, emphasizing the importance of perioperative infection prophylaxis., (Copyright © 2024. Published by Elsevier Inc.)