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Long- term clinical outcomes after cardiac transplantation still remains a challenge because of rejection episodes and the development of coronary vasculopathy. Rejection episode (RE) is a complex immunologic response, associated with the inflammatory signaling network. Allograft inflammatory factor-1 (AIF-1) has an important role in inflammatory process associated with transplantation. The goal was to demonstrate an association between the AIF-1 gene expression and genotype variation with RE. Peripheral blood and endomyocardial specimens were tested by semi-quantitative RT-PCR and immunohistochemistry (IHC) stains for identification of AIF-1 and IL-18 and were analyzed against clinical ISHLT grades for rejection. Sequence-specific primers for AIF-1 gene polymorphism were used to determine the C or the T allele variation in association with RE. The prevalence of CT heterozygous alleles were found significantly higher in patients who were presented with (0) RE during the first 6 months after transplantation as compared with CC alleles. The correlation of having CT alleles versus CC were inversely distributed with the increase in the number of RE. The isoform 2 expression was almost 2-fold higher than isoform 1 or isoform 3 in specimens with grade 3A RE versus specimens with grade 0-1 RE (p<0.001). The AIF-1 and the IL-18 were present in CMCs and in most of the MNCs in the specimens with grade 3A RE. The AIF-1 mRNA transcript expression was increased 5-fold in the biopsy specimens and it was1.7-fold higher than in peripheral blood monocytes in grade 3A RE. The IL-18 expression was increased 4.2-fold in biopsy specimens presented with 3A versus grade 0 (N) RE. Individuals with AIF-1 CC alleles are at a greater risk of developing the early rejection episodes. AIF-1 could serve as a suitable biomarker to monitor cardiac allograft RE through a less invasive procedure.