Abstract: Background and Objectives: Glu298Asp endothelial Nitric Oxide Synthase (eNOS) gene polymorphism results in a reduced bioavailability of Nitric Oxide (NO) and prone to atherosclerosis. Even though there were more than 15 studies conducted on Asian populations investigating the role of this polymorphism in Coronary Artery Disease (CAD), however; the representative data from Malaysia still not clear. The aim of this study was to assess the association between Glu298Asp polymorphism and CAD by conducting a cross-sectional comparative study; in addition to a meta-analytic approach of review to overcome the contradicting evidence arising from conflicting studies in East Asia and South East Asia. Methodology: The study included 185 CAD patients and 188 control participants. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to identify the genotype of the study participants. The results were confirmed by nucleotide sequencing of selected genotypes and the association with CAD was tested using SPSS version 19 with Chi-square test. Execution of meta-analysis involved 23 Asian case-control studies using Revman meta-analysis software version 5.3. Results: The study has demonstrated a significant association between Glu298Asp genotype variants and CAD patients (p<0.001). Asp allele was a significant predictor for CAD ([p = 0.001, OR = 2.186 (1.53-3.125; CI = 95%)]. Through meta-analysis the combined cohort data showed significant Glu298Asp risk to CAD [p<0.0001, OR = 2.41 (1.61-3.59); Heterogeneity test (I2 = 10%, p = 0.33)]. Conclusion: It was concluded that homozygous Asp genotype of Glu298Asp polymorphism potentiates a risk for CAD.