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No consensus has been reached regarding the association beween the -308A/G single nucleotide polymorphism (SNP) in the tumor necrosis factor-α gene (TNFA) and kidney allograft rejection (KAR). Our retrospective case-control study aimed to assess the association of the SNP with KAR in Algerian patients who underwent kidney transplantation. The study enrolled 313 Algerian patients: 58 kidney-transplant recipients without rejection events (PWoR); 58 kidney-transplant recipients with at least one rejection event, with or without graft loss (PWR); and 197 healthy individuals (HI). The TNFA -308A/G SNP was genotyped using a real-time polymerase chain reaction. The results demonstrated that, the frequencies of TNFA -308A allele and AA genotype were higher in the PWR than in the HI groups (p = 0.001, OR = 2.26, CI = 1.33-3.77 and p = 0.0004, OR = 5.53, CI-1.89-16.6, respectively). Furthermore, the frequencies were higher among the PWR than among the PWoR groups (p = 0.001, OR = 3.29, CI = 1.56-7.21 and p = 0.0006, OR = 28.26, CI = 1.62-493.2, respectively), particularly among PWR patients with de novo anti-human leukocyte antigens (HLA) antibodies (PG-a-HLA-Ab). However, the frequency of TNFA -308G allele was lower in the PWR group than in the PWoR group (p = 0.001, OR = 0.3, CI = 0.1-0.64) and the HI group (p = 0.001, OR = 0.44, CI = 0.27-0.44). Our results suggest an association of the TNFA -308A/G alleles with KAR in Algerian patients who underwent kidney transplantation. Carriers of TNFA -308A allele who have PG-a-HLA-Ab might have a higher risk, whereas TNFA -308G allele carriers could have a lower risk of KAR. Thus, therapeutic strategies can be adapted to minimize KAR risk in patients who have a genetic proclivity for increased pro-inflammatory TNF-α activity., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)