Aim: Bipolar disorder (BD) has a complex genetic etiology, with multiple unidentified genes and environmental factors playing important roles in its pathogenesis. A growing body of evidence suggests that reactive oxygen species (ROS) may be crucially involved in the pathogenesis of psychiatric diseases, including BD. The association between paraoxonase 1 (PON1), an important antioxidant enzyme, and development of BD has been scarcely investigated. We thus attempted to examine genetic variants in the PON1 gene, a putative BD susceptibility gene, in patients with bipolar disease and their first-degree relatives. Materials and Methods: The study population consisted of 292 healthy individuals, 199 patients with BD, and 280 unaffected first-degree relatives of the patients. Genotyping of PON1 L55M and Q192R polymorphisms was performed by polymerase chain reaction and restriction enzyme digestion. Results: Patients mostly shared the same PON1 genotypes with their first-degree relatives. The frequency of MM genotype of PON1 L55M polymorphism was lower and that of LM genotype was higher in patients and relatives than healthy controls. PON1 enzyme activities did not differ between patient, relative and healthy control groups but were influenced by PON1 genotype. Conclusion: Our findings indicate an association between the genetic variants of PON1 and BD. The PON1 L55M MM genotype seems to be protective against the development of BD.