OBJECTIVES: To study the association between low compliance with bisphosphonate therapy and the risk of osteoporotic fracture. METHODS: New female users of daily or weekly alendronate or risedronate between 1999 and 2004, aged ≥45 years or with diagnosed post-menopausal osteoporosis were identified from the PHARMO database, including among others linked drug-dispensing and hospitalization data for over two million residents of the Netherlands. Patients were followed from their first bisphosphonate dispensing until their first hospitalisation for osteoporotic fracture, death, or end of the study period. Compliance with bisphosphonates during follow-up was measured over 90-day intervals using the Medication Possession Ratio (MPR), defined as the sum of days' supply of all alendronate and risedronate dispensed to each patient per 90-day interval. Data were analysed univariately and multivariately using time-dependent Cox regression analysis. RESULTS: The study cohort included 8,822 new female users of alendronate or risedronate. During follow-up, 216 osteoporotic fractures occurred, of which 40 excluded fractures during the first 6 months. The percentage of non-compliant patients (MPR <80%) increased from 34% after 6 months to 60% after 3 years of follow-up. Non-compliant bisphosphonate use was associated with a 40% increased risk of fracture (95% CI 4%-90%, adjusted for age and fracture history) compared to compliant bisphosphonate use. This corresponds to a 30% loss of treatment benefit. Classifying compliance into 5 categories, fracture risk gradually increased with poorer compliance (p trend <0.05) to an 80% risk increase with very low compliance (MPR <20%), corresponding to a 45% loss of treatment benefit. CONCLUSIONS: The results of this study show a direct link between level of compliance with oral bisphosphonates and level of fracture risk. Thus, treatment compliance is vital to obtain maximal bone protection. To increase compliance, and therefore treatment benefit, the advent of bisphosphonates with more convenient dosing regimes is important.