Background: The efficacy and safety of a once-daily graded-release diltiazem hydrochloride (GRD) formulation dosed at 10 pm in doses of 180, 360, and 420 mg were compared with placebo and with GRD 360 mg dosed once daily at 8 am in patients (n = 311) with chronic stable angina pectoris. Methods: This was a 3-week multicenter, randomized, double-blind, double-dummy, parallel-group, placebo-controlled trial. Standard Bruce protocol treadmill stress test was performed at baseline and end point between 6 and 8 pm (trough for evening doses) and between 7 and 11 am (trough for morning doses). Results: All GRD evening doses showed a significant (P ≤. 0201) increase in total duration of exercise at trough and a greater significant increase (P ≤. 0002) at peak, compared with placebo. The GRD 360-mg evening dose showed the greatest increase at trough. In contrast, GRD 360-mg morning dose showed an increase in total duration of exercise at trough that was not significantly different (P =. 0555) from placebo am. GRD 360-mg evening dose showed a 4-fold placebo-adjusted improvement compared with GRD 360-mg morning dose between 7 and 11 am. Significant increases (P ≤. 0240) in time to onset of angina were obtained for all evening doses at trough and peak. All GRD doses were well tolerated, and incidence of adverse events for all GRD groups combined was less than that for placebo. Conclusions: Bedtime GRD significantly increases exercise tolerance in patients with angina pectoris over the 24-hour dosing interval. A greater 4-fold placebo-adjusted improvement occurred between 7 and 11 am compared with the same morning dose, coinciding with the period of increased cardiovascular risk. GRD was safe and well tolerated. © 2005, Elsevier Inc. All rights reserved.