OBJECTIVE: To identify determinants of non-compliance with bisphosphonates in women with postmenopausal osteoporosis. By considering the year of the introduction of weekly bisphosphonates important additional information is obtained. METHODS: New fmale users of daily or weekly alendronate or risedronate between 1999 and 2004, aged >or= 45 years were identified from PHARMO RLS, including drug-dispensing and hospitalisation data of > 2 million residents of the Netherlands. One-year compliance with bisphosphonates was measured using the Medication Possession Ratio (MPR). To identify determinants of non-compliance, non-compliant women (MPR < 50%) were compared to compliant women (MPR >or= 80%). The effect of patient age, prescriber, initial dosing regimen, gastrointestinal adverse events, co-medication and fractures on non-compliance was investigated. RESULTS: The study cohort included 8822 new users of bisphosphonates, of whom 5079 (58%) were compliant and 2720 (31%) were non-compliant after 1 year. Only 1023 women (11%) had a MPR between >or= 50% and < 80%. Daily dosing at start, increased number of co-medications and new use of intestinal agents in the year after starting bisphosphonates were independently associated with an increased odds of non-compliance. In contrast, higher age, first prescription from a specialist, osteoporosis related hospitalisation and use of NSAIDs in the year preceding bisphosphonate therapy decreased the odds of non-compliance. CONCLUSION: This study revealed severaldeterminants of non-compliance with bisphosphonates, the best controllable being the type of initial bisphosphonate, with daily dosing leading to more non-compliance than weekly dosing. However, compliance for both regimens is suboptimal, pointing to anunmet medical need.