The pathogenesis of osteonecrosis of the femoral head (ONFH) probably reflects multiple etiologies. Recent studies have explored associations between genetic mutations and/or polymorphisms and ONFH. Annexins (ANXs) have been implicated in many physiological functions, including blood coagulation, inflammation, apoptosis, as well as Ca(2+) homeostasis in bone cells, all of which may be associated with ONFH. The aim of this study was to evaluate the possible association of AnnexinA (ANXA) family gene polymorphisms with ONFH.52 SNPs from three genes of the ANXA family were selected from public databases and genotyped in 443 ONFH patients and 273 control subjects using the Affymetrix Targeted Genotyping 3 K Chip array. The association analysis of genotyped SNPs and haplotypes was performed with ONFH.Among the polymorphisms tested of the ANXA family gene, the rs9324679, rs9324677, rs10037814, and rs11960458 SNPs of the ANXA6 gene were significantly associated with the risk of ONFH in all alternative analysis models (p range; 0.0007-0.049, odds ratio (OR); 0.63-1.72). Further analysis stratified by pathological etiology showed that these SNPs were also associated with the risk of ONFH in at least one subgroup (p range; 0.0017-0.049). Haplotype association analysis showed that several haplotypes were significantly associated with a risk of ONFH, with p values ranging between 0.0005 and 0.049 (OR range; 0.44-1.76).These findings indicate that the polymorphisms of ANXA6 are associated with ONFH. Thus, these polymorphisms may be useful genetic markers to identify high-risk individuals.