Schizophrenia (SCZ) is a complex psychiatric disorder that is strongly influenced by a genetic component. Recent studies suggested that histone deacetylases (HDACs) might increase the expression of several key genes in the brain and may also be associated with susceptibility to SCZ. Among human HDACs, HDAC2 is a critical modulator of gene regulation. Here, we designed a two-stage case-control study to thoroughly examine the association between the HDAC2 gene and SCZ. A total of 19 common single-nucleotide polymorphisms (SNPs) in the region of the HDAC2 gene were analyzed in the test group of 1430 patients and 2862 matched healthy controls. A comparison of the genotype and allele frequencies of the SNPs between cases and controls revealed that three SNPs, rs13212283, rs6568819 and rs9488289, were nominally associated with SCZ. However, we failed to observe any association between these SNPs and SCZ in the validation group consisting of 896 cases and 1815 matched healthy controls. Furthermore, haplotypic analysis also confirmed the negative results. Our results provide preliminary evidence that HDAC2 may not confer susceptibility to SCZ in Han Chinese. Additional genetic studies from a large population are required to obtain more conclusive results.