Most clinicians regard isolated, minor, or nonspecific ST-segment and T-wave (NS-STT) abnormalities to be incidental, often transient, and benign findings in asymptomatic patients. We sought to evaluate whether isolated NS-STT abnormalities on routine electrocardiograms (ECGs) are associated with increased risk of cardiovascular mortality (CM) and all-cause mortality (AM) in a cross-sectional United States population without known coronary artery disease. We included all adults 40 to 90 years of age without known coronary artery disease or risk equivalent based on history and laboratory values, enrolled in the NHANES III from 1988 to 1994, with electrocardiographic data available, and a total follow-up period of 59,781.75 patient-years. NS-STT abnormalities were defined by Minnesota Coding. Subjects were excluded if their mortality data were missing or if they had major electrocardiographic abnormalities, heart rate >120 beats/min, nonsinus rhythm, cardiac infarction/injury score ≥20 on ECG, left ventricular hypertrophy by Minnesota Codes 3.1 and 3.3, or patient-reported history coronary artery disease, congestive heart failure, stroke, diabetes, or peripheral arterial disease. The remaining 4,426 subjects were stratified by presence or absence of NS-STT abnormalities. Mortality was judged based on International Classification of Diseases, Tenth Revision coding linked to the National Death Index. Cox proportional hazard ratio was used for multivariate analysis, showing that CM (hazards ratio 1.71, 95% confidence interval 1.04 to 2.83, p = 0.04) and AM (hazards ratio 1.37, 95% confidence interval 1.03 to 1.81, p = 0.02) were significantly higher in the isolated NS-STT abnormalities group. In conclusion, isolated NS-STT abnormalities on ECG were associated with a higher incidence of CM and AM in this large nationally representative cross-sectional cohort without known coronary artery disease or coronary artery disease risk equivalents.