BackgroundOsteoporosis (OP) is the most prevalent metabolic bone disease. Numerous genetic loci are strongly related to OP.AXIN1is a significant gene that serves an important role in the WNT signaling pathway. The aim of this study was to explore the association between theAXIN1genetic polymorphism (rs9921222) and OP susceptibility.MethodsA total of 101 subjects were enrolled in the study (50 patients with OP and 51 healthy individuals). Genomic DNA was extracted from whole blood using the QIAamp DNA Blood Mini Kit, and theAXIN1gene polymorphism (rs9921222) was genotyped by TaqMan allelic discrimination assays. A logistic regression analysis was used to assess the association between genotypes and OP risk.ResultsWe found thatAXIN1rs9921222 had a significant association with the susceptibility of OP under the homozygote model (TT vs. CC: OR = 16.6, CI = 2.03–136.4,p= 0.009), (CT vs. CC: OR = 6.3, CI = 1.23–31.8,p= 0.027), recessive genetic model (TT vs.TC-CC: OR = 13.6, CI = 1.7–110.4,p= 0.015), and the dominant model (TT-TC vs. CC: OR = 9.7, CI = 2.6–36.3,p< 0.001). Allele T was significantly associated with OP risk (T vs. C: OR = 10.5, CI = 3.5-31.15,p= 0.001). There was a statistically significant difference between genotypes in mean platelet volume (p= 0.004), and platelet distribution width (p= 0.025). In addition, lumbar spine bone density, and femur neck bone density were significantly different between genotypes (p< 0.001).ConclusionAXIN1rs9921222 was associated with OP susceptibility in the Egyptian population and should be considered a potential determinant risk for OP.