Objective. To evaluate adherence to drug therapy among new users of zoledronate and intravenous (IV) ibandronate among US Medicare enrollees. Methods. We used data from the Medicare 5% random sample to evaluate new users of IV zoledronate and IV ibandronate with continuous Part A and Part B fee-for-service coverage. The outcome was adherence as quantified by the proportion of days covered (PDC) measured continuously and dichotomously (≥80%). Followup time extended from 18-27 months for all individuals. Factors associated with low adherence to zoledronate were evaluated with logistic regression. Results. We identified 775 new users of zoledronate and 846 new users of IV ibandronate. For both drugs, 30-48% of the first infusions were given in an outpatient infusion center, not in a physician's office. The mean PDC for zoledronate users was 82%, which was greater than the mean PDC for the IV ibandronate users (58-62% depending on the time period; P < 0.0001). Approximately 30% of zoledronate users did not receive a second infusion. Factors associated with low adherence to zoledronate included older age and receipt of the first infusion in an outpatient infusion center rather than a physician's office. Conclusion. Less frequently dosed IV bisphosphonates have not resolved the problem of suboptimal adherence with prescription osteoporosis medications. Interventions continue to be warranted to improve long-term adherence to osteoporosis treatments. © 2012, American College of Rheumatology.