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Proton pump inhibitors (PPIs) may interfere with calcium absorption through induction of hypochlorhydria but they also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps.To determine the association between PPI therapy and risk of hip fracture.A nested case-control study was conducted using the General Practice Research Database (1987–2003), which contains information on patients in the United Kingdom. The study cohort consisted of users of PPI therapy and nonusers of acid suppression drugs who were older than 50 years. Cases included all patients with an incident hip fracture. Controls were selected using incidence density sampling, matched for sex, index date, year of birth, and both calendar period and duration of up-to-standard follow-up before the index date. For comparison purposes, a similar nested case-control analysis for histamine 2 receptor antagonists was performed.The risk of hip fractures associated with PPI use.There were 13 556 hip fracture cases and 135 386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30–1.59). The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80–3.90; P<.001). The strength of the association increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15–1.30]; 2 years, 1.41 [95% CI, 1.28–1.56]; 3 years, 1.54 [95% CI, 1.37–1.73]; and 4 years, 1.59 [95% CI, 1.39–1.80]; P<.001 for all comparisons).Long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.