Periprosthetic joint infections (PJI) induce an immunosuppressive cytokine profile through an unknown mechanism. Immune checkpoints, like programmed cell death 1 (PD-1) and its ligand (PD-L1), initiate innate immunosuppressive pathways essential for self-tolerance. Several malignancies and chronic infections co-opt these pathways to derive a survival advantage. This study evaluates PD-1/PD-L1 expression in periprosthetic tissue from patients undergoing revision hip or knee arthroplasty for a PJI versus an aseptic failure. PD-1/PD-L1 in the global tissue sample and the high-power microscopic field of maximum expression was analyzed prospectively using immunohistochemistry. Fifteen patients with a PJI (45%) and 16 patients with an aseptic failure (52%) were included. PD-1 expression was uniformly low. Maximum PD-L1 expression was upregulated in patients with a PJI (25%, interquartile range [IQR]:​ 5%–75%) versus an aseptic failure, (8%, IQR:​ 1%–48%, p = 0.039). In the PJI cohort, maximum PD-L1 expression was higher among patients who developed a recurrent PJI (68%, IQR:​ 53%–86% vs. 15%, IQR:​ 5%–70%, p = 0.039). Patients with global PD-L1 over 5% trended toward a near 22-fold increase in the odds of reinfection (odds ratio [OR]:​ 21.9, 95% confidence interval [CI]:​ 0.9–523.5, p = 0.057) and patients with maximum PD-L1 over 20% trended toward a 15-fold increase in the odds of reinfection (OR:​ 15.0, 95% CI:​ 0.6–348.9, p = 0.092). These results support immune checkpoint upregulation as a mechanism of PJI-induced local immune dysfunction. Future studies should confirm PD-L1 as a risk factor for reinfection in larger cohorts.