Cardiac function was measured at rest and during exercise in 9 patients with sickle-cell anemia (SS) and coexisting homozygous alpha thalassemia-2 (alpha thal-2). Results were compared with 18 sickle cell patients with normal alpha globin genes, who were matched to the study group by age, gender, and size, and to published normal values. SS alpha thal-2 patients were less anemic: 9.9 f 1 .O vs 8.2 f 1.2 gm/dl for SS alone (P < .05). Left ventricular dimensions were normal in SS alpha thal-2 (4.9 f 0.7 cm), but increased in SS (5.4 f 0.7, cm P =.05) (normal range, 3.7-5.6 cm). Left ventricular wall thickness was, however, dramatically increased in the SS alpha thal-2 patients (free wall, 1.8 2 0.6 cm; septum, 1.6 f 0.4 cm), though SS controls had normal wall thickness (free wall, 1.0 f 0.2 cm; septum, 1 .O f 0.2 cm, P < .001) (normal range, 0.6-1.1 cm). At rest, Doppler indices of systolic function were not significantly different between sickle groups and normal values. SS alpha thal-2 patients did have abnormal diastolic filling at rest, as evidenced by a reduced ratio of early/late diastolic filling, 1.4 2 0.3 vs. 2.0 f 0.5 for SS controls (P < .Ol), and 1.8 2 0.4 for normals. An analysis of covariance suggested that this abnormality persisted after taking into account the previously demonstrated hypertrophy. During exercise, SS alpha thal-2 patients had higher heart rates and blood pressures than SS controls in spite of performing the same or less work. This resulted in a higher double product (an estimate of oxygen consumption) in SS alpha thal-2 patients (37,470 2 2,310 mm Hg-BPM) than in SS controls (33,310 f 1,490 mm Hg-BPM, P < .01). Work capacity, peak heart rate, and blood pressure were all abnormally decreased in both sickle-cell groups when compared to normal. Cardiac abnormalities noted at rest and during exercise in SS alpha thal-2 patients suggest a role of microvascular occlusion and a protective effect of decreased hemoglobin.