Background: Attenuated niacin skin flush response and an increased inflammatory response indicate abnormal functioning of the metabolic cascade of cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2) enzymes and/or abnormal COX-2 enzyme activity. Abnormal activity of cPLA2/COX-2 metabolic cascade and/or COX-2 enzyme might contribute to abnormal dopaminergic neurotransmission, which is implicated in both the etiology of schizophrenia and nicotine dependence. In the current study we investigated whether the rs689466 polymorphic variant of the PTGS2 gene for COX-2 might influence the risk for nicotine dependence among Croatian patients with schizophrenia and schizoaffective disorder. Furthermore, we revealed whether the interaction between smoking and the rs689466 polymorphism underlies clinical features of the illness, such as the age at first hospitalization and Positive and Negative Syndrome Scale Psychopathology (PANSS) data. Patients and methods: Our study group consisted of 190 patients (males/females: 104/86). Genotyping was performed by PCR-RFLP method in the Department of Biology and Medical Genetics, School of Medicine, University of Rijeka. Results: Genotype and allele frequencies between smokers and nonsmokers did not differ significantly in any male or female patients (P > 0.05). Furthermore, the interaction between the PTGS2 genotype and smoking did not contribute to the severity of PANSS psychopathology neither among males nor among females (P > 0.05), whereas the interaction between the PTGS2 genotype and smoking on the time of disease onset was revealed only for female patients. An earlier onset, observed for female smokers carrying the G-alelle in their PTGS2 genotypes (PTGS2-GG homozygous and PTGS2-AG heterozygous) in comparison to nonsmoking PTGS2-GG homozygous females, contributed mostly to this finding. Conclusion: Statistically significant effect of the rs689466 polymorphism was observed only in female patients; in this patient group, the rs689466 polymorphism, in interaction with smoking, modulates the age at disease onset to a lesser extent.