Angiotensin-converting enzyme (ACE) inhibitors effectively interfere with the renin-angiotensin system and exert various beneficial actions on vascular structure and function beyond their blood pressure-lowering effects. Zofenopril, a potent sulphydryl ACE inhibitor, is characterized by high lipophilicity, sustained cardiac ACE inhibition, and antioxidant and tissue protective activities. Its ancillary properties, such as antioxidant activity and cardiovascular (CV) protection, make this drug potentially suitable for the treatment and prevention of certain CV diseases. The Survival of Myocardial Infarction Long term Evaluation trials have demonstrated that the early administration of zofenopril to patients with acute myocardial infarction is associated with a significant reduction in the 6-week occurrence of major CV events in high-risk patients with anterior non-thrombolyzed myocardial infarction. The fixed combination of zofenopril-hydrochlorothiazide (HCTZ) 30/12.5 mg/day is approved for the management of mild-to-moderate hypertension in different European countries. In clinical trials comparing zofenopril-HCTZ with each agent administered as monotherapy, combination therapy was clearly more effective in normalizing blood pressure (BP). In addition, combination therapy provided sustained and consistent BP control over the entire 24 hour dosing interval. The efficacy and safety profile of zofenopril-HCTZ highlights that this combination is a potentially useful addition to currently available therapy for patients with BP inadequately controlled by monotherapy, as well as for patients who require more rapid and intensive BP control.