Carvedilol is indicated for the treatment of essential hypertension and mild-to-severe chronic heart failure, as well as the reduction of cardiovascular mortality in clinically stable post–myocardial infarction patients with left ventricular dysfunction. Carvedilol is a racemic mixture of R(+) and S(−) enantiomers that combines β₁-, β₂-, and ⍺₁-adrenoceptor blockade. For all indications, the immediate-release (IR) formulation of carvedilol is taken twice daily. A controlled-release (CR) formulation of carvedilol that allows once-daily dosing has recently been developed. In this double-blind, parallel-group, crossover study, 122 patients with essential hypertension were randomly allocated to receive low and high doses of carvedilol or placebo. Patients received either a constant low dose (CR 20 mg once daily or IR 6.25 mg twice daily) or were titrated to a high dose (CR 80 mg once daily or IR 25 mg twice daily) before being crossed over to an equivalent dose of the alternative formulation. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles were compared between patients receiving carvedilol CR and carvedilol IR. The PK profiles for R(+)- and S(−)-carvedilol for the 2 formulations were equivalent (based on area under the curve, maximum plasma concentration [C_max], and trough drug concentration). Consistent with an extended-release formulation, carvedilol CR delayed C_max by 3.5 hours compared with carvedilol IR. For both carvedilol CR and IR, the attenuation of exercise-induced heart rate in patients with hypertension was maintained over the entire 24-hour period, and the 2 formulations demonstrated equivalent β₁-blocking effects at trough (end of the dosing interval [PD_min]), suggesting that the rate of absorption does not interfere with the PD effect. In this first direct comparison of carvedilol CR and IR in subjects with hypertension, fewer adverse events were reported while subjects were receiving carvedilol CR (59.1% overall) compared with carvedilol IR (77.5% overall). This was true regardless of dose received. Headache was the most commonly reported adverse event for subjects receiving either formulation of carvedilol and placebo. Importantly, dizziness and headache were reported less often when subjects received carvedilol CR. This is the first study to show that both formulations had comparable β₁-adrenergic blockade in patients with essential hypertension under steady-state conditions. Notably, carvedilol CR provides consistent β₁-adrenergic blockade over 24 hours with a once-daily dose.