INTRODUCTION: Apolipoprotein E (APOE) genotypes influence the phenotype of several neurodegenerative disorders including Alzheimer's and Parkinson disease and may affect schizophrenia pathogenesis. This study was undertaken to determine the association between APOE gene polymorphisms and schizophrenia in the Saudi population. MATERIAL AND METHODS: APOE allele and genotype frequencies were studied in 380 Saudi subjects including schizophrenia patients and matched controls using polymerase chain reaction (PCR) and reverse-hybridization techniques. RESULTS: The frequencies of the APOE allele epsilon2 and genotypes epsilon2/epsilon3 and epsilon2/epsilon4 were significantly higher in the schizophrenia patients as compared to controls, suggesting that the epsilon2 allele and its heterozygous genotypes may increase the susceptibility to schizophreniIn contrast, the frequencies of the epsilon3 allele and epsilon3/epsilon3 genotype were lower in patients as compared to controls, suggesting a protective effect of APOE epsilon3 for schizophreniThis study indicated that APOE epsilon4 was differentially associated with schizophrenia depending on the symptoms as the frequency of the epsilon4 allele was significantly higher in schizophrenia patients with positive symptoms. By contrast, no significant association between APOE epsilon4 and schizophrenia patients with negative symptoms was observed. Genotypes epsilon2/epsilon2 and epsilon4/epsilon4 were absent in patients and controls. Moreover, the age of onset was significantly lower in patients with the APOE epsilon2/epsilon3 genotype. There was no significant difference in the frequencies of APOE alleles and genotypes between male and female schizophrenia patients. CONCLUSIONS: The results of this study clearly show that APOE alleles and genotypes are associated with risk of developing schizophrenia and early age of onset in Saudis.