In this case-control study, we analyzed the association between three single nucleotide polymorphisms (SNPs) in the CASC15 gene (rs6939340 A>G, rs4712653 T>C, and rs9295536 C>A) and neuroblastoma susceptibility in the Guangdong and Henan populations of China. We genotyped and analyzed 118 cases and 281 control subjects from Henan province and combined them with previously published data from the Guangdong population. In the Henan population, only the rs6939340 G>A variant homozygote AA was associated with decreased neuroblastoma risk [AA vs. GG: adjusted odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23-0.98; P=0.045]. All three polymorphisms, individually and in combination, were associated with decreased neuroblastoma susceptibility in the Guangdong population. Moreover, subjects carrying 1-3 of these protective genotypes had lower neuroblastoma susceptibility than non-carriers (adjusted OR=0.65, 95% CI=0.51-0.84, P=0.0007). These results show that all three genetic variants of CASC15 identified in a genome-wide association study (GWAS) decrease neuroblastoma risk in two distinct Chinese populations.