OBJECTIVES: To identify determinants of non-compliance with bisphosphonate therapy in women with post-menopausal osteoporosis. METHODS: Data were obtained from the PHARMO Record Linkage System, which includes linked drug-dispensing records and hospital records for more than two million individuals in defined areas of The Netherlands. New female users of alendronate or risedronate in the period 1 January 1999 - 30 June 2004, aged °Ý 45 years or with diagnosed post-menopausal osteoporosis were included in the study. One-year compliance with the initial dosing regimen was measured using the Medication Possession Ratio (MPR). To identify determinants of non-compliance, non-compliant patients (MPR < 50%) were compared to compliant patients (MPR °Ý 80%). The effect of dosing regimen, patient age, prescriber, co-medication and fractures on non-compliance was investigated. For independent factors increasing non-compliance the Population Attributable Risk percentage (PAR%) was determined. RESULTS: The study cohort included 4699 (53%) compliant and 3089 (35%) non-compliant users of daily or weekly bisphosphonates. A total of 1034 (12%) patients had a MPR °Ý 50% and <80% over the first year. Use of daily bisphosphonates, number of different co-medications used, and use of gastrointestinal medication during the first year were associated with an increased risk of non-compliance (OR 3.1, 95% CI 2.7-3.5; OR 1.8, 95% CI 1.3-2.3 for >10 different co-medications; and OR 1.2; 95% CI 1.1-1.4, respectively). Corresponding PAR% were 42%, 14% and 6%, respectively. In contrast, higher age, first prescription from a specialist, use of NSAIDs and hospitalization for osteoporosis or osteoporotic fracture in the year preceding bisphosphonate therapy independently decreased the risk of non-compliance. CONCLUSIONS: These results indicate that daily, rather than a weekly, dosing regimen is the most important independent determinant of non-compliance with bisphosphonates. However, compliance for both regimens can be considered to be suboptimal and leaves room for improvement.