To investigate whether haematopoietic stem cells in patients with sickle cell (SS) disease might be altered, we examined the number and cycling status of 5‐week long‐term culture‐initiating cells (LTC‐ICs) and in vitro multilineage colony‐forming cells (CFCs) present in the blood of a large and clinically diverse group of SS patients. The concentrations of both of these cell types per ml of blood varied over a wide range in individual patients, but, on average, were significantly elevated above normal values (∼sevenfold and 15‐fold respectively) and to an even greater extent than the lineage‐restricted CFCs in the same samples. Wide variations in the concentration of circulating progenitors, particularly the LTC‐ICs, were also seen over time (in concert with changes in the white blood cell count) in SS patients. [³H]‐Thymidine suicide assays showed most of the CFCs and LTC‐ICs in SS blood to be quiescent like their counterparts in normal blood. However, by comparison with historical data, the SS progenitors could be recruited into the cycle more quickly (i.e. within 2 vs. 3 d), thus showing the same kinetics of activation exhibited by ‘mobilized’ progenitors from patients given chemotherapy and exogenous growth factors. Taken together, these findings implicate previously documented increases in endogenous Steel factor, interleukin 3 and granulocyte–macrophage colony‐stimulating factor levels in SS patients in the establishment of a chronically mobilized progenitor phenotype.