Combinations between an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) and hydrochlorothiazide (HCTZ) are among the recommended treatments for hypertensive patients uncontrolled by monotherapy. Four randomized, double-blind, parallel group studies with a similar design, including 1469 hypertensive patients uncontrolled by a previous monotherapy and with ≥1 cardiovascular risk factor, compared the efficacy of a combination of a sulfhydryl ACE inhibitor (zofenopril at 30 or 60 mg) or an ARB (irbesartan at 150 or 300 mg) plus HCTZ 12.5 mg. The extent of blood pressure (BP)-lowering was assessed in the office and over 24 h. Pleiotropic features of the treatments were evaluated by studying their effect on systemic inflammation, organ damage, arterial stiffness, and metabolic biochemical parameters. Both treatments similarly reduced office and ambulatory BPs after 18-24 weeks. In the ZODIAC study a larger reduction in high sensitivity C reactive protein (hs-CRP) was observed under zofenopril (-0.52 vs. +0.97 mg/dL under irbesartan, p = 0.001), suggesting a potential protective effect against the development of atherosclerosis. In the ZENITH study the rate of carotid plaque regression was significantly larger under zofenopril (32% vs. 16%; p = 0.047). In the diabetic patients of the ZAMES study, no adverse effects of treatments on blood glucose and lipids as well as an improvement of renal function were observed. In patients with isolated systolic hypertension of the ZEUS study, a slight and similar improvement in renal function and small reductions in pulse wave velocity (PWV), augmentation index (AI), and central systolic BP were documented with both treatments. Thus, the fixed combination of zofenopril and HCTZ may have a relevant place in the treatment of high-risk or monotherapy-treated uncontrolled hypertensive patients requiring a more prompt, intensive, and sustained BP reduction, in line with the recommendations of current guidelines.