BACKGROUND There is a need for novel skin antiseptic agents to combat the health-care burdens associated with surgical site infection (SSI) and bacterial resistance. The purpose of this proof-of-principle pilot study was to investigate the potential of the phenolic compound protocatechuic acid (PCA) as a topical antimicrobial for surgical skin antisepsis. METHODS The Kirby-Bauer method of disc diffusion was used to investigate the in vitro antimicrobial activity and comparative effectiveness of PCA and 7 related compounds against SSI pathogens. To explore the in vivo efficacy of topical PCA for providing deep, penetrating skin antisepsis, living Cutibacterium acnes was intradermally injected into the skin of female BALB/c mice. Mice were assigned to treatment with daily applications of topical PCA at 3 doses (78, 39, and 19.5 mM) or no treatment (n = 2 mice per group). After 96 hours, infected skin samples were harvested to compare mean C. acnes counts by treatment. RESULTS Compared with other polyphenols, PCA demonstrated the broadest spectrum of antimicrobial activity against tested SSI pathogens, including drug-resistant organisms. At 96 hours following infection, the mean C. acnes burden in untreated mice was 6.65 log colony-forming units (CFUs) per gram of skin. Compared with the untreated group, daily topical application of 78 mM of PCA was associated with a significantly lower C. acnes CFU burden in mice skin (mean, 5.51 log CFUs per gram of skin; p = 0.0295). Both lower dosages of topical PCA failed to show an effect. CONCLUSIONS PCA demonstrated laboratory efficacy against pathogens implicated in SSI, including drug-resistant organisms. In vivo, topical PCA demonstrated dose-dependent skin penetration and antimicrobial activity against mouse skin C. acnes loads. Human clinical studies exploring the antimicrobial efficacy of topical PCA for preoperative shoulder skin antisepsis are warranted. CONCLUSIONS Topical PCA may have the potential to improve current shoulder SSI treatment and prevention protocols.