Although achieving blood pressure (BP) control is critical to improve cardiovascular prognosis in hypertensive patients, many of them fail to attain the targets. Most patients with hypertension need more than one antihypertensive agent to achieve the goals. Combination therapy is required when monotherapy fails to attain BP objectives (< 140/90 mmHg in general hypertensive population; < 130/80 mmHg in high-risk groups) and as a first-line treatment in certain situations, such as markedly elevated BP values, high or very high cardiovascular risk patients or when lower targets are warranted. The advantages of combination therapy are well documented with the potential for increased antihypertensive efficacy as a result of different mechanisms of action, and a lower incidence of adverse effects because of the lower doses used and the possible compensatory responses. The inhibition of the renin-angiotensin system appears to be very beneficial in the treatment of patients with hypertension. Olmesartan medoxomil 20 mg/hydrochlorothiazide 12.5 mg is the latest combination of an angiotensin receptor blocker and a diuretic approved for treatment of hypertension. The aim of this manuscript is to update the published data about the efficacy and safety of this fixed combination.