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Oxidative stress and free radical-induced toxicity have been implicated in the pathophysiology of schizophrenia. In this study, we examined paraoxonase (PON1)-55/192 polymorphisms and PON1 activity in patients with schizophrenia, first-degree relatives of schizophrenic patients, and healthy controls.This study consisted of 292 healthy participants, 267 unrelated patients with schizophrenia and 311 first-degree relatives of schizophrenic patients. PON1 55 (rs 854560) and PON1 192 (rs 662) polymorphisms were performed by restriction fragment length polymorphism.The frequencies of the QQ and LL genotypes were significantly overpresented in controls compared with those of schizophrenic patients and their relatives. In contrast, the RR genotype was more prevalent in patients than their relatives and healthy controls. The frequencies of the LM and QR genotypes in relatives were higher than controls. Serum PON1 activities of controls were significantly higher when compared with both schizophrenic patients and their relatives. The RR and LL genotypes were associated with a significantly increased PON1 activity as compared with QR or QQ and MM or LM genotypes, respectively, in all groups.This is the first study that shows the association between PON1-55/192 polymorphisms and schizophrenia. Our data suggest that the subjects carrying R allele or RR genotype might be susceptible to schizophrenia and subjects with QQ or LL might be protected against schizophrenia. First-degree relatives of schizophrenic patients have higher heterozygote genotypes, suggesting that this group can shift either to patient or control group depending on their allele types and environmental factors. PON1 genetic variations are also associated with PON1 activities. Reduced PON1 activity in patients and their relatives might result from the combined effects of more than one polymorphic variant in PON1 or other genes and/or increased oxidative stress, supporting the hypothesis that reactive oxygen species-mediated cellular damage might contribute to the neuropathology of schizophrenia.