Autism spectrum disorder (ASD) is one of neurodevelopmental disorders with highly heritability. Recently, abnormality at the synapse is found to be important etiology of ASD. SHANK3 gene is suggested as a strong candidate gene for the pathogenesis of ASD, because it is essential for normally synaptic structure and function. We performed a case-control study to identify association between rs9616915 of the SHANK3 gene and ASD in a Chinese population. Genomic DNA was extracted from oral swabs samples of 212 patients and 636 controls and the SNP genotypes were determined by a polymerase chain reaction-restriction fragment length polymerase assay. Significant difference in genotype distribution of rs9616915 was observed between cases and controls by Pearson's chi (2) test (chi (2) = 6.92, P = 0.031). Genetic analysis of heterozygous model, dominant model and additive model showed an association of the C allele of the rs9616915 with ASD (e.g., additive model, OR 0.582, 95 % CI 0.359-0.942, P = 0.028). In conclusion, our results suggested that this commonly genetic variant in SHANK3 gene strikingly decreased the risk of ASD in China.