Single nucleotide polymorphisms (SNPs) in TCF7L2 (Transcription Factor 7-Like 2) reportedly affect susceptibility to schizophrenia (SCZ). We examined the association between TCF7L2 polymorphisms and SCZ susceptibility in a Chinese Han population. Six SNPs were genotyped in 499 SCZ patients and 500 healthy individuals, after which their associations with SCZ were evaluated using the Chi-squared test and genetic model analyses. We observed that the allele A of rs12573128 is associated with an increased SCZ risk (odds ratio [OR] = 1.33, 95% confidence interval [CI]: 1.08-1.63, P = 0.006, adjusted P = 0.030). The AA genotype of rs12573128 was associated with a higher SCZ risk than the GG genotype, before and after adjustment for sex and age (adjusted OR = 2.97, 95% CI: 1.49-5.92, P = 0.002). In addition, SNP rs12573128 was associated with 1.47-fold, 2.64-fold and 1.50-fold increases in SCZ risk of in dominant, recessive and additive model, respectively (adjusted OR = 1.47, 95% CI = 1.09-1.99, P = 0.012; Bonferroni adjusted P = 0.030). adjusted OR = 2.64, 95% CI = 1.34-5.18, P = 0.005 and adjusted OR = 1.50, 95% CI = 1.17-1.93, P = 0.002, respectively). These results suggest rs12573128 is significantly associated with an increased risk of SCZ in the Chinese Han population.