Context: Bisphosphonates are the mainstay of anti-osteoporotic treatment and are commonly used for a longer duration than in the placebo-controlled trials. A link to development of atypical subtrochanteric or diaphyseal fragility fractures of the femur has been proposed, and these fractures are currently the subject of a U.S. Food and Drug Administration review. Objective: Our objective was to examine the risk of subtrochanteric/diaphyseal femur fractures in long term users of alendronate. Design: We conducted an age- and gender-matched cohort study using national healthcare data. Patients: Patients were alendronate users, without previous hip fracture, who began treatment between January 1, 1996, and December 31, 2005 (n = 39,567) and untreated controls, (n = 158,268). Main outcome measures: Subtrochanteric or diaphyseal femur fractures were evaluated. Results: Subtrochanteric and diaphyseal fractures occurred at a rate of 13 per 10,000 patient-years in untreated women and 31 per 10,000 patient-years in women receiving alendronate [adjusted hazard ratio (HR) = 1.88; 95% confidence interval (CI) = 1.62-2.17]. Rates for men were six and 31 per 10,000 patient-years, respectively (HR = 3.98; 95% CI = 2.62-6.05). The HR for hip fracture was 1.37 (95% CI = 1.30-1.46)) in women and 2.47 (95% CI = 2.07-2.95) in men. Risks of subtrochanteric/diaphyseal fracture were similar in patients who had received 9 yr of treatment (highest quartile) and patients who had stopped therapy after the equivalent of 3 months of treatment (lowest quartile). Conclusions: Alendronate-treated patients are at higher risk of hip and subtrochanteric/diaphyseal fracture than matched control subjects. However, large cumulative doses of alendronate were not associated with a greater absolute risk of subtrochanteric/diaphyseal fractures than small cumulative doses, suggesting that these fractures could be due to osteoporosis rather than to alendronate.