INTRODUCTION: Periprosthetic joint infection (PJI) is a challenging complication following total joint arthroplasty. A two-stage exchange has been the gold standard in the treatment of chronic PJI. However, when this fails, further treatment options become limited. In patients who fail two-stage exchange, the reinfecting organism is different from the original in 50 to 80% of occurrences. This study aimed to understand reinfection patterns in an attempt to better predict reinfecting organisms to improve the management of PJI. METHODS: A retrospective query of our institution's PJI registry identified 185 patients (188 procedures, 110 knees, 78 hips) who underwent a first-time two-stage exchange for culture-positive chronic PJI of total knee and hip arthroplasties from January 2010 to December 2020. Patients who had polymicrobial infections, culture-negative results, or fungal infections were excluded. The primary outcome variable was reoperation for reinfection and comparing the index organism to the reinfecting organism. RESULTS: Of the 188 procedures, 31 (16.5%) failed due to reinfection. Among reinfections, 30 (96.8%) were gram-positive, with Staphylococcus aureus species accounting for 22 (71.0%) of cases. The most common organisms cultured were for methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococcus, and streptococcus. Of reinfections, 19 (61.3%) had a different organism, eight (25.8%) had the same organism, and four (12.9%) were culture-negative. Patients experiencing reinfection were significantly younger (P = 0.012), with no other patterns or predictors identified. CONCLUSION: The majority of reinfections following a two-stage exchange for PJI occur with a different organism than the index infection. We did not find a reliable method to predict the reinfecting organism based on the initial infecting organism alone. However, the same four gram-positive organisms were the most frequently encountered in both the primary infection and the reinfection. Further research is required to understand factors contributing to reinfection and help guide prevention strategies.