Paraoxonase-1 (PON1) is the antioxidant marker of high-density lipoproteins protecting against atherosclerosis and coronary artery disease (CAD) phenotype. The purpose of the present study was to determine whether the PON1 gene rs854560 polymorphism (163T>A) is associated with CAD in Polish population. rs854560 was genotyped in 494 subjects: 248 patients with premature CAD and 246 blood donors as a control. We found that the risk of CAD was significantly higher in TT homozygotes than in A allele carriers (OR = 1.87, p = 0.041). The synergistic effect between the TT genotype and cigarette smoking was observed (SIM = 9.81; SI = 14.70). The relative increase in risk from interaction between factors was over 37 (RERI = 36.13). The PON1 polymorphism did not modulate the risk of CAD in response to exposure to other traditional risk factors. In conclusion, the rs854560 polymorphism may modulate the risk of CAD in response to cigarette smoking in Polish population. Carriers of TT genotype seem to be particularly at risk of CAD, when exposed to cigarette smoking.