OBJECTIVES: To assess whether new users of antihypertensive therapy could benefit from using a single-pill, fixed-dose combination drug compared with separate pills to improve their adherence to therapy. METHODS: Data from the Integrated Primary Care Information database in the Netherlands (NL) and 30 Italian (IT) general practitioners with automated medical records were used. Patients aged =30y with mild-to-moderate hypertension and =3 cardiovascular risk factors or prior cardiovascular events who were experienced or new users of antihypertensives in June 2003-June 2004 (NL) or June 2004-June 2005 (IT) were selected. Patients were followed until October 2005 (NL) or February 2006 (IT) when they completed a questionnaire concerning adherence to their therapy. Treatment adherence (percentage of days covered [PDC]) was also calculated from the prescription records. RESULTS: A total of 729/1473 (49.5%) (NL) and 1320/1602 (82.4%) (IT) completed the questionnaire. Of these, 101 (NL) and 47 (IT) patients were new users of antihypertensives. Reasons for not taking medications were side effects, ineffectiveness and forgetfulness, which scored highest in the NL. In Italy, forgetfulness and side effects were ranked highest. The median PDC for antihypertensive drugs was 57% (NL) and 69% (IT), less than 40% (NL) and 42% (IT) had PDC >80%. Partial (PDC 20-80%) and poor (PDC<20%) adherence occurred frequently in newly treated hypertensive patients. Approximately 35% (NL) and 70% (IT) of the respondents stated that they would be less or much less likely to miss a dose with a single pill combination therapy. The likelihood to miss a dose with single-pill treatment was not associated with the prescription-derived PDC levels, but highly associated with self-reported level of adherence. CONCLUSION: Patients newly treated with antihypertensive drugs with additional cardiovascular risk factors may benefit from a single pill. Screening of those who may benefit should be based on self-reported adherence rather than PDC levels.