PURPOSE: Discontinuation with treatment is a major problem in the treatment of hypertension. The objective of our study was to assess the association between non-compliance and discontinuation in patients who started using antihypertensive monotherapy. METHODS: A nested case-control study within a cohort of new users of antihypertensive drugs between 1st January 1999 and 31st December 2002 was performed. 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 discontinued their use of antihypertensive monotherapy and were not switched to other antihypertensive treatment, controls stayed on their initially prescribed monotherapy. Conditional logistic regression was used to calculate odds ratios (OR) and their 95% confidence intervals (CI). RESULTS: In a cohort of 39,714 new users of antihypertensive drugs, we identified 9111 cases and 9111 matched controls. The percentage of non-compliant patients (compliance < 80%) among cases and controls was 14.0% and 5.8%, respectively [OR 2.86 (95%CI: 2.52-3.24)]. Patients who used less than 90 days had a higher risk on discontinuation [OR 3.10 (95%CI: 2.67-3.59)] than patients who used more than 90 days [OR 2.28 (95%CI: 1.79-2.92)]. The association was generally similar among males and females, among the different types of antihypertensives and among the different age groups. CONCLUSION: In patients who start antihypertensive monotherapy, non-compliance is often followed by discontinuation of this antihypertensive treatment. The pharmacy medication history is a valuable tool for physicians to identify patients who have a high risk on discontinuation with antihypertensive treatment.