BACKGROUND: Non-compliance is an important factor in lack of control of blood pressure. Uncontrolled blood pressure, as well as patients’ complaints about the prescribed medication, may lead to modification of the initially prescribed antihypertensve drug regimen. The objective of this study was to assess the association between non-compliance and change in medication regimen. METHODS: A nested case-control study within a cohort of new users of antihypertensive drugs between 1 January 1999 and 31December 2002. We used data from the PHARMO database, a record linkage system containing drug-dispensing records from community pharmacies and linked hospital discharge records of approximately 950 000 subjects. Cases were subjects whose initial drug regimen was modified. Controls did not undergo such a modification. Conditional logistic regression was used to calculate odds ratios (OR) and their 95% confidence intervals (CI), and to adjust for confounders. RESULTS: In a cohort of 39 714 new users of antihypertensive drugs, we identified 11 937 cases and 11 937 matched controls. The percentage of non-compliant patients (compliance < 80%) among cases and controls was 5.1 and 3.6%, respectively [OR 1.39 (95% CI: 1.22-1.58)]. The association is stronger in females [OR 1.64 (95%CI: 1.37-1.94)] than in males [OR 1.14 (95% CI: 0.94-1.40)] and stronger if the duration of episode of use is longer than 6 months. CONCLUSION: Non-compliance is significantly associated with the occurrence of change in antihypertensive medication regimen. Pharmacists and physicians can use pharmacy data, although data tend to overestimate actual compliance, to assess and improve compliance with antihypertensive drugs, before modifying treatment regimens.