For 80 children with relapsed acute lymphoblastic leukemia, glucocorticoid receptor (GR) levels were lower in blast cells from patients who developed relapse while receiving chemotherapy (p = 0.03) and in those who failed reinduction treatment (p = 0.07). Serial determinations of GR at diagnosis and at relapse in blast cells from 41 patients disclosed various changes in receptor content, which were not related to the initial GR levels, the immunophenotype of blast cells or number of relapses. Six of 9 patients for whom reinduction therapy failed and only 7 of 32 patients in whom subsequent remission was induced had decreased GR levels at relapse (p = 0.018). One patient failed reinduction despite a sharp increase in GR level. Although a decrease in GR levels between diagnosis and relapse is associated with steroid resistance, other mechanism(s) can also be responsible for the development of steroid resistance in childhood leukemia.