Schizophrenia (SZ) is a complex psychiatric disorder with a strong genetic component. The serotonin transporter (SERT), encoded by solute carrier family 6 member 4 (SLC6A4), regulates synaptic concentrations of serotonin and thereby strongly influences perception, mood, emotion, behavior, and cognition, all of which are severely disturbed in SZ. Two variable numbers of tandem repeat (VNTR) polymorphisms and several single nucleotide polymorphisms (SNPs) spread throughout SLC6A4 are involved in both neuropsychiatric diseases (including SZ) and personality traits. In this study, case-control association analysis was performed in the Chinese-Han population to identify additional allelic variants of the SLC6A4 gene that may confer susceptibility to SZ. Ten relatively common SNPs (minor allele frequency > 5%) were genotyped in 528 paranoid SZ patients and 528 control subjects. Significant associations were found between SZ and the allele and genotypic frequencies of rs140700G/A (p = 2.45 × 10− 12, 2.34 × 10− 11, respectively). The frequency of the A allele was lower in SZ patients (17.7%) than in controls (30.9%; OR = 1.93, 95%CI = 1.58–2.36). In five factor analysis of the positive and negative syndrome scale (PANSS) scores of first episode SZ patients, mean negative factor score (F2,249 = 3.986, p = 0.02) and depression/anxiety factor score (F2, 249 = 8.766, p = 2.11 × 10− 4) were significantly different among the rs140700G/A genotypes, with both scores higher for genotype AA than AG + GG. The rs140700G/A allele of SLC6A4 is strongly associated with SZ susceptibility and symptom expression in the Chinese-Han population.