Background Fractures of the talus in the elderly are rare and usually result from high-impact injuries, suggesting only minor age-related bone structure changes. However, total ankle replacement failures with age often result from talar subsidence, suggesting age-related bone loss in the talus. Despite a number of histological analyses of talar microarchitecture, the effects of age and sex on talar microarchitecture changes remain poorly defined.Questions/purposes The aim of this study was to analyze changes or differences in the trabecular microarchitecture of the talus with regard to (1) age and (2) sex. Methods Sixty human tali were harvested from 30 patients at autopsy of three different age groups (20-40, 41-60, 61-80 years). The specimens were analyzed by radiography, micro-CT, and histological analysis. Given that there was no difference between the left and right talus, static histomorphometric parameters were assessed in three regions of interest of the right talus only (body, neck, head; n = 30). Results The talar body, neck, and head were affected differently by age-related changes. The greatest loss of bone volume with age was seen in the talar body (estimate: À0.239; 95% confidence interval [CI], À0.365 to À0.114; p \ 0.001). In the talar neck (estimate: À0.165; 95% CI, À0.307 to À0.023; p = 0.025), bone loss was only moderate and primarily was the result of reduction in trabecular thickness (estimate: À1.288; 95% CI, À2.449 to À0.127; p = 0.031) instead of number (estimate: À0.001; 95% CI, À0.005 to À0.003; p = 0.593). Bone structure changes were independent of sex. Conclusions Age-related bone structure changes predominantly occur in the talar body, which poses a potential risk factor for total ankle replacement loosening. The moderate changes in the talar neck might explain the persistent low incidence of talar neck fractures with age.