Background: Paraoxonase-1 (PON1), a glycoprotein associated with serum high-density lipoprotein (HDL), has a central role in metabolizing lipid peroxides, exhibiting antiatherogenic properties. The polymorphism p.Q192R has been previously associated with coronary artery disease (CAD) susceptibility and clopidogrel response. Purpose: We aimed at investigating the association of PON1 p.Q192R with CAD and clopidogrel response in Colombian population. Patients and Methods: The study was conducted among 163 patients diagnosed with CAD and treated with clopidogrel. The allele frequencies for the PON1 192Q and 192R alleles were determined in cases and Latin-American controls obtained from the public database gnomAD (n = 17,711). Response to clopidogrel was determined by assessing the platelet function using the INNOVANCE PFA-200 System. We determined the association between PON1 p.Q192R polymorphism, increased susceptibility to CAD and high on-treatment platelet reactivity (HPR) by using odds ratio (OR) and 95% confidence interval (CI) on four genetic models. Results: The allele frequencies for the PON1 192Q and 192R alleles were 0.60 and 0.40, respectively. The allele distribution was found to be statistically different from the control group and other ethnic groups. The allele 192R was positively associated with decreased susceptibility to CAD under a dominant model (OR, 0.58; 95% CI, 0.42–0.8; P andlt; 0.01). We found no association between the polymorphism and HPR. Conclusion: We propose that PON1 p.Q192R is a potentially useful marker for CAD susceptibility in the Colombian population and lacks association with HPR under clopidogrel treatment.