Abstract Background Estrogen is believed to play an important role in the central nervous system (CNS) and exert a protective role against schizophrenia. Estrogen receptor alpha (ESRα) mediates the biological action of estrogen. Rs2234693 and rs9340799, single nucleotide polymorphisms of ESRα, may be related to many psychiatric disorders, while their association with schizophrenia has not been clarified. Methods Genotypes rs2234693 and rs9340799 were detected in 303 schizophrenic patients and 292 healthy controls in a Chinese population. The positive and negative syndrome scale (PANSS) was used to estimate symptoms and therapeutic effects. The association of these polymorphisms with schizophrenia and clinical characteristics was analyzed by the chi-square test, analysis of variance, and others. Results The distribution of genotypes and allele frequencies of rs2234693 and rs9340799 exhibited no significant differences between patients and controls, while haplotypes consisting of these polymorphisms had significant differences. For 2234693, T-allele carriers had an earlier age at onset. CC-homozygote carriers had a higher general psychopathology score and its percentage reduction in male and paranoid patients, respectively. CC-homozygote carriers had a higher tension (G4) and poor impulse control (G14) score, mainly in paranoid patients. Furthermore, patients with the CC homozygote had higher reductions of G4 and G14 scores when treated by aripirazole and risperidone, respectively. Conclusions Haplotypes consisting of these two polymorphisms in ESRα may be strongly associated with schizophrenia. The rs2234693 was related to age at onset, general psychopathology, G4 and G14 symptoms, even the therapeutic effect in different groups.