Recently a new variant of Creutzfeldt-Jakob disease, a human prion disease, with prominent psychiatric manifestations in the early stage was identified, suggesting that human prion disease may be associated with mental disorders. Furthermore, a novel missense mutation with asparagine-to-serine substitution at codon 171 of the human prion gene (N171S) was identified in a family with severe psychiatric symptoms. This finding provides further clue that the prion gene may be a susceptibility gene for certain psychiatric disorders. We systematically sequenced the protein-coding and untranslated exons of prion gene in 62 Han Chinese schizophrenic patients with positive family history from Taiwan. We identified two polymorphisms that alter amino acid sequences, a methionine/valine at codon 129 (M129V) and a glutamate/lysine at codon 219 (E219K), respectively. Further comparison of the genotype, allele and haplotype frequency distributions of these two polymorphisms between 234 schizophrenic patients and 100 non-psychotic controls, however, did not reveal significant differences between two groups. Besides, no other mutations in the prion gene were identified in these 62 patients. Hence, our results suggest that the prion gene may not play a major role in conferring susceptibility to schizophrenia.