OBJECTIVES: To quantify the impact of a less frequent bisphosphonate regimen (weekly v daily) on compliance and persistence. METHODS: Data on bisphosphonate naïve post-menopausal women in the US were derived from an administrative claims database (1997-2003) covering 30 health plans. In the UK and Germany data were derived from local Mediplus databases (2001-2005) containing 2.5 million and 1.5 patients respectively. Women were grouped into two cohorts; once daily (OD - alendronate 5mg or 10mg and risedronate 5mg) and once weekly (OW - alendronate 70mg and risedronate 35mg). They were followed for at least 12 months from initial prescription. Compliance was estimated as a Medication Possession Ratio (MPR) and persistence as the number of days from initial prescription to the date of discontinuation of therapy. RESULTS: The number of women evaluated was 2,741 from US (OW = 731, OD = 2010), 5962 from UK (OW = 5102, OD = 860) and 288 from Germany (OW = 144, OD = 144). Mean age in each country was 73 years. OW users had a significantly higher MPR than OD users (US: 56.3% v 37.7%, UK: 70.3% v 51.7%, Germany: 51.7% v 37.7%, p <0.0001). OW users also had a significantly higher persistence than OD users (US: 227 v 185 days, UK: 228 v 186 days, Germany: 227 v 172 days, p <0.0001). More women stayed on weekly compared to a daily regimen during the 12 month follow up (US: 44.2% v 31.7%, UK: 43.6% v 33.3%, Germany: 46.5% v 27.8%, p <0.0001). CONCLUSIONS: Similar findings in different healthcare systems confirm that compliance and persistence with bisphosphonate treatment is improved substantially with a less frequent dosing regimen. A further decrease may help patients use bisphosphonate treatment more regularly and longer term to maximise the therapeutic goal of reducing fracture rates.