The incidence and hemodynamic changes associated with ST-segment depression during adenosine stress testing are poorly defined. To examine this, 550 consecutive patients who underwent adenosine perfusion testing were evaluated for the development of ST-segment depression. At least 1 mm of horizontal or downsloping depression developed in 82 patients (15.9%) and was observed with similar frequency in patients with normal scans and those with only fixed defects. ST depression developed in 58 of 242 patients with reversible defects (sensitivity = 24%) and in only 24 of 275 patients without reversible defects (specificity = 91%). Its presence was highly predictive of reversible perfusion defects (predictive accuracy = 71%). Similar findings were observed in patients with and without ECG evidence of left ventricular hypertrophy. Patients with ST depression had perfusion defects in more vessel distributions, had more severe defects, and had a greater increase in heart rate during adenosine infusion. Thus ST-segment depression occurs infrequently during adenosine infusion but is specific for and predictive of myocardial ischemia, as evidenced by reversible perfusion scan defects. Patients with ST depression have more severe disease and develop faster heart rates during infusion, which could result in decreased coronary perfusion during diastole allowing for the development of myocardial ischemia.