Abstract: Background: The purpose of this work was to study the association between the PON1 L55M and Q192R polymorphisms and bipolar I disorder in Tunisian patients and to explore their relation to the sociodemographic, clinical and therapeutic characteristics of this disease.Patients and methods: Our study included 109 patients with bipolar I disorder and 110 controls aged 39.4±11.8 and 37.3±9.2years, respectively. L55M and Q192R of the PON1 gene polymorphisms were determined by multiplex polymerase chain reaction.Results: Significant difference was detected in the distribution of the genotype frequencies of L55M and Q192R polymorphisms (χ²=6.32, df=2, p=0.04; χ²=10.15, df=2, p=0.006 respectively) between patients and controls. We noted significant association between bipolar I disorder and QR and RR genotypes (OR 2.06, CI 95% 1.10–3.84, p=0.02; OR 1.72, CI 95% 1.07–2.75, p=0.02 respectively) and between this disease and LM and MM genotypes (OR 2.22, CI 95% 1.19–4.15, p=0.012; OR 3.04, CI 95% 1.60–5.77, p=0.01 respectively). There were no significant differences in gender, age at onset, illness episode and treatment among all genotypes. However, Q192R polymorphism was significantly associated with age and patients with RR genotype were the youngest.Conclusion: Bipolar I disorder was significantly associated with L55M and Q192R polymorphisms, suggesting that these polymorphisms may play a role for development of bipolar I disorder. There was no significant association between the clinical and therapeutic characteristics of this population and these polymorphisms. Further studies are required to clarify the implication of these polymorphisms in the pathophysiology of bipolar I disorder.