Abstract Context: Femoral shaft cortical thickening has been mentioned in reports of atypical subtrochanteric and diaphyseal (S/D) femur fractures, but it is unclear whether thickening precedes fracture or results from a preceding stress fracture and what role bisphosphonates might play in cortical thickening. Objective: Our objective was to examine the relationship of cortical thickness to S/D fracture risk as well as establish normal reference values for femoral cortical thickness in a large population-based cohort of older women. Design: Using pelvic radiographs obtained in 1986–1988, we measured femoral shaft cortical thickness 3 cm below the lesser trochanter in women in the Study of Osteoporotic Fractures. We measured this in a random sample and in those with S/D fractures and femoral neck and intertrochanteric fractures. Low-energy S/D fractures were identified from review of radiographic reports obtained between 1986 and 2010. Radiographs to evaluate atypia were not available. Analysis used case-cohort, proportional hazards models. Outcomes: Cortical thickness as a risk factor for low-energy S/D femur fractures as well as femoral neck and intertrochanteric fractures in the Study of Osteoporotic Fractures, adjusting for age and bone mineral density in proportional hazards models. Results: After age adjustment, women with thinner medial cortices were at a higher risk of S/D femur fracture, with a relative hazard of 3.94 (95% confidence interval = 1.23–12.6) in the lowest vs. highest quartile. Similar hazard ratios were seen for femoral neck and intertrochanteric fractures. Medial or total cortical thickness was more strongly related to fracture risk than lateral cortical thickness. Conclusions: In primarily bisphosphonate-naive women, we found no evidence that thick femoral cortices placed women at higher risk for low-energy S/D femur fractures; in fact, the opposite was true. Women with thin cortices were also at a higher risk for femoral neck and intertrochanteric fractures. Whether cortical thickness among bisphosphonate users plays a role in atypical S/D fractures remains to be determined.