The frequency and clinical relevance of rare pathogens at the site of periprosthetic infections of the hip and knee joint and their antibiotic resistance profiles have not yet been assessed in-depth. We retrospectively analyzed all periprosthetic hip and knee joint infections that occurred between 2016 and 2020 in a single center in southwest Germany. Among 165 infections, 9.7% were caused by rare microorganisms such as Veilonella sp., Pasteurella sp., Pantoea sp., Citrobacter koseri, Serratia marcescens, Parvimonas micra, Clostridium difficile, Finegoldia magna, Morganella morganii, and yeasts. No resistance to piperacillin/tazobactam, carbapenemes, fluoroquinolones, or gentamicin was observed. Some bacteria displayed resistance to ampicillin, ampicillin/sulbactam, and cefuroxime. We present follow-up data of patients with infections due to rare pathogens and discuss the importance of close, interdisciplinary collaboration between orthopedic surgeons and clinical microbiologists to carefully select the most appropriate anti-infective treatment regimens for the increasing number of patients with such infections.