Genetics and epi-genetic alterations trigger the development of non-alcoholic fatty liver disease (NAFLD). Patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is known to be a key regulator of lipid metabolism in the liver and is expressed in both adipocytes and hepatocytes. The aim is to evaluate the association between two single nucleotide polymorphism (SNPs) of PNPLA3 gene and NAFLD, and their relation to the degree of hepatic steatosis and fibrosis. Eighty individuals were selected and divided into two groups according to ultrasound finding of steatosis; a test group of 40 patients with bright liver and a group of 40 healthy subjects with normal liver. Steatosis was quantified by controlled attenuation parameter (CAP). Fibrosis assessment was done by fibrosis-4 (FIB-4), NAFLD fibrosis score, Fast score and Fibroscan. Complete blood count, liver enzymes, fasting blood glucose, and lipid profile were performed. Genomic DNA was isolated from blood. rs738409 C>G SNP of the PNPLA3 gene was determined via PCR-RFLP while rs139051 (A>G) polymorphism of the PNPLA3 gene was detected using TaqMan genotyping assay. GG genotype was significantly related to the presence of NAFLD (P=0.043) while the homozygous wild type (CC) was the common genotype among healthy controls. There was a significant association between the presence of the G allele (46.3%) in the PNPLA3 (I148 M) polymorphism and the presence of NAFLD (P <0.001). However, rs139051 PNPLA3 AG genotype was the most frequent genotype in both patients with NAFLD (82.5%) and healthy controls (85%). No significant correlation was found between any of the variants of both genotypes and the degrees of both steatosis and fibrosis detected by CAP and Fibroscan respectively. In conclusion, PNPLA3 gene polymorphism rs738409 but not rs139051 is significantly associated with NAFLD patients with simple steatosis. This blood test could serve as a screening tool for simple steatosis which warrants earlier follow-up and further intensive therapies.