IntroductionPeriprosthetic joint infection (PJI) is a devastating complication following total joint replacement (TJR).Cutibacterium acnes(C. acnes) is a low virulent skin commensal, commonly found during TJR revision surgery for “aseptic” causes. The purpose of the present study was to report the treatment outcomes of patients withC. acnescontamination or infection in the presence of a TJR treated with a revision surgery ± implant exchange ± prolonged (≥ 8 weeks) postoperative antibiotics.MethodsMedical records of patients with at least one positiveC. acnesculture in intraoperative tissue samples or sonication fluid from a TJR revision surgery between January 2005 and December 2014 were retrospectively evaluated. The primary endpoint was infection eradication according to Delphi criteria. The diagnostic accuracy of preoperative TJR aspiration regarding the diagnosis ofC. acnesPJI was also investigated.ResultsA total of 52 TJR (28 shoulders, 17 hips, 7 knees) in 52 patients (35 males, 17 females) with an average age of 63 ± 11 (33–86) years were included. At an average follow-up of 67 ± 33 (24–127) months, the infection eradication ofC. acnesPJI was 97% regardless of the surgical treatment or administration of prolonged postoperative antibiotics. The incidence of unsuspectedC. acnesPJI was 28.8%. The sensitivity and specificity of preoperative joint aspiration in detectingC. acnesPJI were 59% and 88%, whereas the PPV and NNV were 83% and 67%, respectively.ConclusionInfection eradication ofC. acnesPJI was very high at a minimum follow-up of 24 months, suggesting thatC. acnesPJI could be adequately treated with a combination of revision surgery and prolonged postoperative antibiotics. The preoperative diagnosis ofC. acnesPJI might be challenging with more than one-quarter of patients presenting without suspicion ofC. acnesPJI. The appropriate treatment of patients with a single positive culture remains still unclear. A negative TJR aspiration should not rule out aC. acnesPJI, especially in the presence of clinical correlates of infection.Level of evidenceRetrospective case–control study, Level III.IRB approvalKantonale Ethikkommission Zürich, BASEC Nr.:2017-00567.