To understand the effects of single- and multiple-drug combinations for hypertension on the risk of adverse clinical outcomes, the authors analyzed data from the International Verapamil SR/Trandolapril Study (INVEST). This trial randomized 22,576 hypertensive patients with coronary artery disease to sustained-release verapamil or to atenolol as initial agents, followed by trandolapril or hydrochlorothiazide. Electronically collected prescription data from INVEST during 61,835 patient-years were analyzed using a Cox proportional hazards model with nine covariates (randomization strategy, four average daily dose terms, two ratios measuring the proportion of time the first two drugs in the treatment arm were coprescribed, and two interaction terms). Increasing doses of atenolol and sustained-release verapamil were associated with decreasing risk of the composite primary outcome (death, myocardial infarction, or stroke). Combination therapy with two drugs (verapamil/trandolapril or atenolol/hydrochlorothiazide) reduced the risk of primary outcome compared with monotherapy (verapamil or atenolol), and triple therapy (verapamil/trandolapril/hydrochlorothiazide or atenolol/hydrochlorothiazide/trandolapril) further reduced the risk.