Introduction: A periprosthetic joint infection (PJI) is a major complication of arthroplasty. Treatment of PJI consists of surgical debridement with or without the exchange of the implant and long... Show moreIntroduction: A periprosthetic joint infection (PJI) is a major complication of arthroplasty. Treatment of PJI consists of surgical debridement with or without the exchange of the implant and long-term antimicrobial treatment. Rifampicin is regarded as one of the cornerstones of antimicrobial treatment for staphylococcal PJI, but the exact role of rifampicin for PJI in different clinical scenarios remains to be elucidated.Areas covered: In this perspective article, an overview is provided of in vitro, in vivo and clinical studies that were the basis of the current guidelines and recommendations for rifampicin use in daily practice for PJI. Controversial issues on indication, dosing, timing, duration, and antibiotic drug interactions will be addressed. Finally, the most urgent clinical questions on rifampicin use that need answering in the nearby future will be formulated.Expert Opinion: Many inquiries remain concerning the exact indications and clinical use of rifampicin in PJI. Randomized controlled trials are needed to answer these questions. Show less