Isolated systolic hypertension (ISH), defined as systolic blood pressure (SBP) ≥140 mm Hg and diastolic blood pressure (DBP) <90 mm Hg, in younger and middle-aged adults is increasing in prevalence. The aim of this study was to assess the risk for cardiovascular disease (CVD) with ISH in younger and middle-aged adults. CVD risks were explored in 15,868 men and 11,213 women 18 to 49 years of age (mean age 34 years) at baseline, 85% non-Hispanic white, free of coronary heart disease (CHD) and antihypertensive therapy, from the Chicago Heart Association Detection Project in Industry study. Participant classifications were as follows: 1) optimal-normal blood pressure (BP) (SBP <130 mm Hg and DBP <85 mm Hg); 2) high-normal BP (130 to 139/85 to 89 mm Hg); 3) ISH; 4) isolated diastolic hypertension (SBP <140 mm Hg and DBP ≥90 mm Hg); and 5) systolic diastolic hypertension (SBP ≥140 mm Hg and DBP ≥90 mm Hg). During a 31-year average follow-up period (842,600 person-years), there were 1,728 deaths from CVD, 1,168 from CHD, and 223 from stroke. Cox proportional hazards models were adjusted for age, race, education, body mass index, current smoking, total cholesterol, and diabetes. In men, with optimal-normal BP as the reference stratum, hazard ratios for CVD and CHD mortality risk for those with ISH were 1.23 (95% confidence interval [CI]: 1.03 to 1.46) and 1.28 (95% CI: 1.04 to 1.58), respectively. ISH risks were similar to those with high-normal BP and less than those associated with isolated diastolic hypertension and systolic diastolic hypertension. In women with ISH, hazard ratios for CVD and CHD mortality risk were 1.55 (95% CI: 1.18 to 2.05) and 2.12 (95% CI: 1.49 to 3.01), respectively. ISH risks were higher than in those with high-normal BP or isolated diastolic hypertension and less than those associated with systolic diastolic hypertension. Over long-term follow-up, younger and middle-aged adults with ISH had higher relative risk for CVD and CHD mortality than those with optimal-normal BP.