STUDY OBJECTIVE:To estimate the relativerisk ofhipfracture associated withproton pump inhibitor(PPI) use in a population withoutmajorrisk factors.DESIGN:A two-phase, matched, nested case-control study.DATA SOURCE:United Kingdom General Practice Research Database (GPRD).PATIENTS:Phase 1 identified 4414 casepatients(aged 50-79 yrs) with an incidenthipfracture between 1995 and 2005 who had at least 2 years of recorded history in the GPRD; each case was matched by age, sex, and index date (date of first-timehipfracture for cases, same date for matched controls) to up to 10 controls who did not havehipfracture. Phase 2 included the 1098 casepatientsidentified as having nomajormedicalrisk factorsforhipfracture (as assessed in phase 1) and a new set of 10,923 controls withoutmajorrisk factorsforhipfracture matched by sex, age, index date, and duration of history in the GPRD.MEASUREMENTS AND MAIN RESULTS:In phase 1, we identifiedmajormedicalrisk factorsforhipfracture. In phase 2, we restricted the study to casepatientswith none of theserisk factorsand matched them to new controls, who also had none of therisk factors. Data on use of PPIs were collected and compared between the groups. The relativerisk(RR) forhipfracture amongpatientswho received any PPI prescription was 0.9 (95% confidence interval 0.7-1.1) compared with those with no PPI prescription. We found no evidence of an increasedrisk ofhipfracture with increased PPI use. The RR estimates were similar in both sexes and in all age subgroups. No specific PPI was associated with an increasedrisk ofhipfracture.CONCLUSION:Use of PPIs does not increase therisk ofhipfracture inpatientswithoutmajorrisk factors. The difference in results between our study and that of another, which indicated that PPI use increases therisk ofhipfracture, may be due to residual confounding or effect modification in the latter study.