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Histamine interacts with histamine H4 receptor (HRH4) to impact antipsychotic response.Pharmacogenetic information about this receptor could therefore be useful in developing individualized therapy.The aim of this investigation was to clarify whether polymorphisms at human HRH4 gene alter risperidone efficacy.We genotyped 5 tag-single nucleotide polymorphisms of the HRH4 gene and analyzed their asso-ciation with the reduction in Positive and Negative Syndrome Scale (PANSS) scores in a group of 113 Chinese Hart patients with schizophrenia who were following an 8-week period of risperidone monotherapy.Using W2, analysis of variance, haplotype, and receiver operating characteristics analysis, we found that HRH4 common variant rs4483927 is significantly associated with risperidone efficacy and that its TT genotype predicts poor therapeutic response both on the positive, negative, and general subscales and on the total scale of PANSS scores (P =0.017, 0.019, 0.021, and 0.002, respectively, in analysis of variance).Our results provide the first evidence that an HRH4 polymorphism may be a molecular marker for the prediction ofrisperidone efficacy and suggest novel pharmacologic links between HRH4 gene and treatment of schizophrenia.