In vitro platelet aggregation responses to epinephrine and ADP were significantly lower in patients with sickle cell disease when compared to age- and sex-matched normal subjects. Platelet aggregation responses were reduced in all patients regardless of clinical status. Measurement of circulating platelet aggregates showed normal values in patients with sickle cell disease in steady state or with infection alone, but a significant increase in others with acute vaso-occlusive crises. Recovery from vaso-occlusion was associated with a decline in circulating platelet aggregates. This study suggests that in vivo platelet activation may result in “tired” platelets which are refractory to epinephrine and ADP stimulation in vitro.