The purpose of this study was to investigate the correlation between single necleotide polymorphisms (SNPs) of human epidermal growth factor receptor-2 (HER2) gene with osteosarcoma susceptibility in Chinese Han population. 90 patients with osteosarcoma and 100 healthy controls who were frequency-matched with the former by age and gender were enrolled for a case-control study. 5 SNPs of HER2, namely rs2952155, rs1810132, rs2952156, rs1136201 and rs1058808, were tested by Sequenom time of flight mass spectrometry technique. The linkage disequilibrium and haplotype were analyzed using haploview software. The risk intensity of osteosarcoma was expressed by odds ratio (OR) with 95% confidence interval (CI) which was calculated by chi-squared text. Hardy-Weinberg equilibrium (HWE) was also evaluated by chi-squared text. HER2 gene rs1136201 and rs1058808 polymorphisms were associated with the increased risk of osteosarcoma (P=0.04 and 0.02, respectively). Allele G in rs1136201 was 1.67 higher risk for osteosarcoma in cases than the control group (OR=1.67, 95% CI=1.11-2.51) and G allele of rs1058808 polymorphism also significantly increased osteosarcoma susceptibility (OR=2.06, 95% CI=1.27-3.22). The haplotype analysis showed that haplotype C-T-G-G might be a susceptible haplotype to osteosarcoma (OR=1.74, 95% CI=1.01-3.00). HWE test was eligible in controls (P>0.05). HER2 gene rs1136201 and rs1058808 polymorphisms and haplotype C-T-G-G may be related to osteosarcoma susceptibility in Chinese Han population, indicating that the interaction of gene polrmorphism plays an role in osteosarcoma risk.