Objective: Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine, some studies reported that TNF-alpha gene plays important role in the pathogenesis of SONFH. And the polymorphisms of TNF-alpha were presented as risk factors for steroid-induced osteonecrosis of the femoral head (SONFH). Meanwhile, various environment factors involve in the pathogenesis of SONFH. Our study aimed to investigate the interaction effect of TNF-alpha polymorphisms and hypoxia factor on SONFH. Methods: 120 patients with SONFH and 100 healthy people, matched with the cases on age and sex, participated in this study. DNA was extracted from all participants. According to previous studies, genotyping of TNF-alpha polymorphisms (rs1800629, rs1799964 and rs1800630) was tested with the method of PCR-RDB (Reverse Dot Blot). Environmental factors were also chose. Logistic regression analysis was used to analyze the interaction between TNF-alpha polymorphisms and environment factors on SONFH. Results: The polymorphisms of rs1800629 and rs1800630 were significantly associated with SONFH (OR: 3.70, 9.93). Patients with hypoxia history were found higher (65.00%) compared with the healthy controls (43.00%). For the person with hypoxic history, GG and AG+AA genotypes of rs1800629 could increase their risk to suffer SONFH (OR: 2.12, 3.78). If the patients with the variant genotypes of rs1800630 experienced hypoxia state, then the risk for SONFH increased 2.41 folds. Conclusion: We concluded that the onset of SONFH was influenced by TNF-alpha and hypoxia history. There existed strong interaction between TNF-alpha and hypoxia history.