Systemic arterial hypertension constitutes the leading cause of mortality worldwide, and affects people living at different altitudes above sea level (AASL). AASL has a major impact on cardiovascular function and various biologic pathways that regulate blood pressure–related phenotypes, but whether it affects the clinical response to antihypertensive therapy is unknown. The hemodynamic adaptations observed among lowlanders acutely exposed to high altitude (HA) is distinct from those observed among HA dwellers. However, the phenotypic patterns of hypertension and the response to standard antihypertensive agents among adults chronically exposed to different AASL are poorly understood. The authors describe the protocol for the INTERVENCION trial, a randomized clinical trial designed to assess the effects of three first-line antihypertensive monotherapies (a thiazide diuretic, an angiotensin receptor blocker, and a calcium channel blocker) on peripheral and central blood pressure, in-office blood pressure, and ambulatory blood pressure hemodynamics of hypertensive patients living at different AASL (low altitude, intermediate altitude, and high altitude). The primary end point is the reduction in 24-hour brachial systolic blood pressure. The INTERVENCION trial will provide the first clinical trial data regarding the influence of AASL on the response to antihypertensive monotherapy, as well as the hemodynamic characteristics of arterial hypertension at different AASL.