Objective.–To assess the association between first myocardial infarction and the use of antihypertensive agents. Design and Setting.–We conducted a population-based case-control study among enrollees of the Group Health Cooperative of Puget Sound (GHC). Patients and Methods.–Cases were hypertensive patients who sustained a first fatal or nonfatal myocardial infarction from 1986 through 1993 among women and from 1989 through 1993 among men. Controls were a stratified random sample of hypertensive GHC enrollees, frequency matched to the cases on age, sex, and calendar year. All 623 cases and 2032 controls had pharmacologically treated hypertension. Data collection included a review of the ambulatory medical record and a brief telephone interview of consenting survivors. Antihypertensive therapy was assessed using the GHC's computerized pharmacy database. Results.–The first analysis included only the 335 cases and 1395 controls initially free of cardiovascular disease. Compared with users of diuretics alone, the adjusted risk ratio of myocardial infarction was increased by about 60% among users of calcium channel blockers with or without diuretics (risk ratio=1.62; 95% confidence interval [CI], 1.11 to 2.34; P=.01). The second analysis was restricted to 384 cases and 1108 controls who were taking either a calcium channel blocker or a [beta]-blocker. Among these subjects, the use of calcium channel blockers compared with [beta]-blockers was associated with about a 60% increase in the adjusted risk of myocardial infarction (risk ratio=1.57; 95% CI, 1.21 to 2.04; P<.001). While high doses of [beta]-blockers were associated with a decreased risk of myocardial infarction (trend P=.04), high doses of calcium channel blockers were associated with an increased risk (trend P<.01). Conclusions.–In this study of hypertensive patients, the use of short-acting calcium channel blockers, especially in high doses, was associated with an increased risk of myocardial infarction. Ongoing large-scale clinical trials will assess the effect of various antihypertensive therapies, including calcium channel blockers, on several important cardiovascular end points. Until these results are available, the findings of this study support the current guidelines from the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure that recommend diuretics and [beta]-blockers as first-line agents unless contraindicated, unacceptable, or not tolerated.; People taking calcium channel blockers appear to have a greater risk of heart attack than those taking other classes of drugs used to lower blood pressure. Researchers studied the records of 623 patients who had heart attacks while taking antihypertensive medication and 2,032 patients who were treated for high blood pressure but did not have heart attacks. The patients ranged in age from 30 to 79. Patients taking high doses of short-acting calcium channel blockers had a 60% higher risk of heart attack compared to patients taking beta-blockers or angiotensin-converting enzyme (ACE) inhibitors. The risk, however, was small for patients on low doses of calcium channel blockers.