The aim of this study was to identify polymorphisms in the histamine N-methyltransferase (HNMT) gene in Chinese and to assess their relationship with HNMT activity. One hundred and ninety-two unrelated subjects were recruited. HNMT polymorphisms were screened by direct sequencing with purified polymerase chain reaction products comprising all six exons, plus splice junctions, as well as approximately 2 kb of the 5'-flanking region (5'-FR). Erythrocyte HNMT activity was previously measured by radiochemical microassay. A total of 11 single nucleotide polymorphisms (SNPs) were identified, among which six SNPs had variant allele frequencies greater than 5%. Of the six common SNPs, three (-1637T>C, -463T>C and -411C>T) were located in 5'-FR, one (314C>T) in coding exons, and two (939A>G and 1097A>T) in the 3'-untranslated region (3'-UTR). Most of these common SNPs were in linkage disequilibrium. Genotype-phenotype correlation analyses were performed for those common SNPs in 5'-FR and 3'-UTR. In males, no significant association was found between HNMT activity and these non-coding SNPs. However, in females, the -1637T>C or -463T>C tended to be associated with decreased HNMT activity, whereas the 939A>G or 1097A>T appeared to be correlated with increased enzymatic activity. HNMT polymorphisms differ considerably between Chinese and American. The common SNPs in 5'-FR (-1637T>C and -463T>C) and 3'-UTR (939A>G and 1097A>T) might conditionally regulate the activity of HNMT, or might be genetically linked to unknown mutation(s) underlying the HNMT phenotypic variance.