Background: Spontaneous bacterial peritonitis (SBP), a common and severe complication in patients with advanced liver cirrhosis, assumed that can result from bacterial translocation from the intestine. Mutations in the Nucleotide-binding oligomerization domain containing 2 (NOD2) genes contribute to bacterial translocation and subsequently increased susceptibility to spontaneous bacterial peritonitis. Aim: The aim of this study was to investigate the association between the NOD2 gene variants and SBP in Egyptian patients with post-HCV cirrhotic ascites. Patients and Methods: Overall, 90 patients with post-HCV cirrhotic ascites were genotyped for the three common NOD2 variants, 1007fs, R702W and G908R and underwent diagnostic paracentesis, the ascitic fluid was analyzed for polymorphonuclear leucocytic count (PMN) and bacterial culture results. Results: NOD2 risk alleles were detected in 13 patients (14.4%) and all patients were heterozygous for one NOD2 polymorphism. Patients with SBP were more often carriers for NOD2 risk alleles than patients without SBP (Odds ratio (OR) = 4.7, P= 0.027). The NOD2 risk variant R702W was significantly higher in patients with SBP than other variants (OR= 6.2, P=0.021). Univariate analysis revealed that predictors of SBP were a previous episode of SBP, recent variceal hemorrhage and the presence of a NOD2 risk allele. Multivariate analysis confirmed NOD2 polymorphism (OR = 3.7, p = 0.03) as independent predictor of SBP. Conclusion: NOD2 risk variants specifically R702W are associated with SBP susceptibility in the Egyptian patients with cirrhosis.