Multiple threshold values have been proposed for synovial leukocyte count (white blood cell count) and synovial neutrophil percentage (percent polymorphonuclear neutrophils) in the diagnosis of periprosthetic joint infection (PJI). The objective of this study was to elucidate the variability of these criteria under diverse patient/surgical settings. Hip PJIs yield higher synovial white blood cell counts and percent polymorphonuclear neutrophils than knee PJIs. Periprosthetic joint infection of failed unicompartmental knee arthroplasty produces a higher white blood cell count than that of failed total knee arthroplasty. Synovial white blood cell count and percent polymorpho-nuclear neutrophils PJI thresholds also vary in patients with antibiotic cement spacers and depend on the timing from primary arthroplasty (<6 weeks vs >6 weeks). Similarly, test results should be carefully interpreted for patients with comorbidities so that PJI is not missed or falsely identified. [Orthopedics. 2021;44(3):e320-e325.].