The possibility that myocardial ischemia may be associated with chest pain during painful crises was evaluated prospectively in 20 patients (11 women and nine men) with sickle cell disease (19 SS, 1 S beta + thalassemia). Sixteen of 20 (80%) had abnormal ECGs, 7 (35%) had transient ST-T wave changes, and 3 (15%) had persistent ST-T wave changes, both consistent with ischemia; 6 (30%) had nonspecific ST-T changes, and 4 (20%) had normal tracings. Serum enzymes (CK, SGOT, LDH) were abnormal in 16 of 19 (84%); 1 had CK-MB detected, (5%) and 1 had LDH1 to LDH2 reversal. All 10 Tc-99m pyrophosphate scans performed were negative; 4 of 6 (66%) thallium-201 scans had focal defects, and 5 of 8 (63%) radionuclide angiograms (MUGAs) had focal wall motion abnormalities. Three of 8 (38%) MUGAs showed cardiac dilation, diffuse hypokinesis, and reduced ejection fractions. Thus, myocardial damage may be a potentially serious complication of patients with sickle cell anemia who present with chest pain during painful crises. Studies are indicated to define the significance and pathophysiology of these observations.