A number of genetic variants have been identified in the lipoprotein lipase (LPL) gene. We aimed to investigate the possible associations between LPL gene and apolipoprotein C3 (APOC3) gene polymorphisms with coronary artery disease (CAD) and its severity, as well as the interaction between these polymorphisms and classical risk factors. The HindIII variant of LPL and APOC3 were genotyped in 156 CAD patients and 154 subjects as a control group. We found that the odds ratio (OR) estimating the effect of joint exposure to H2H2 genotype of LPL and S2S2 genotype of APOC3 was significantly higher than the OR estimating the effect of each factor in the absence of the other. The present study points to a synergistic interaction between H2H2 genotype of LPL gene and S2S2 genotype of APOC3 gene that leads to increased severity of CAD. Smoking, low HDL, and diabetes increased the severity of CAD in patients carrying these risky genotypes.