Abstract BACKGROUND AND AIMS Kidney transplantation is the only cure for patients with end-stage renal disorders. Therefore, protecting these patients from transplant rejection is a critical lifesaving project after transplantation. Graft rejection and BK polyoma virus (BKPyV) associated nephropathy (BKVAN) is one of the common causes of graft loss among kidney transplant recipients (KTRs) through activating innate and adaptive immunity. In between, the role of cytokines is very perilous in handling the immune responses against rejection, such as IL-27, and in this study, it is tried to investigate the role of IL-27 and its receptor (IL-27R; WSX-1) in KTRs. METHOD EDTA-treated blood samples were collected from 90 KTRs that were divided into three equal groups of BKV-inactive/non-reject (G1), BKV-active/non-reject (G2) and BKV-inactive/reject (G3), after being monitored by real-time PCR (Taq-Man) in plasma. A total of 30 normal individuals were considered as healthy control group (G0). A real-time PCR (SYBR Green) technique is used to determine the expression level of studied genes. RESULTS The results of gene expression comparisons showed that the expression level of IL-27 was significantly higher in G1 compared with the G2 group. Analysis also showed that the difference in the expression level of genes between the G3 and G0 groups was statistically significant. Also, the same comparison between the G1 and G0 groups showed a significant difference. The area under the ROC curve (AUC) showed that IL-27 is a significant discriminating molecule between all three studied groups of patients. The analyses revealed that the expression level of studied genes has a significant correlation with viral load. Finally, the ROC analysis showed that IL-27 and IL-27R seem to be important molecules for discrimination between G2 and G3 patient groups. CONCLUSION It is not easy to determine the IL-27 pro-inflammatory function as an endogenous regulatory mechanism, which might be one of the reasons for the immune system’s inability to inhibit the BKPyV reactivation in KTRs. Therefore, knowing the fact that in vivo loss of IL-27 signalling would not make drastic defects in immune development, turns IL-27 an attractive candidate for therapeutic research. It is important to consider the role of cytokines in different rejection conditions and the role of some cytokines should be more studied, such as IL-27 and IL-27R in course of kidney rejections, which happens especially between 2 weeks and 2 months after transplantation.