The production of fetal hemoglobin was investigated in plasma clot cultures of adult bone marrow cells from normal donors and from individuals with homozygous HbS or HbC disease. Synthesis of gamma and beta chains was assessed either by 35S-methionine labeling of cultures and measurement of the radioactivity incorporated into the methionine- containing tryptic peptides of the gamma and beta subunits or by 3H- leucine labeling and measurement of the radioactivity incorporated into the globin chains of Hbs F0 and A0 isolated by ion-exchange chromatography. The cultures from all individuals responded with increased production of HbF. Cultured cells from subjects without a hemoglobinopathy produced an average of 8.2% gamma chains (range 3.1%– 20.3%), while cultured cells from subjects homozygous for HbS or HbC produced an average of 16.6% gamma chains (range 12.2%–20.4%). These findings indicate that fetal Hb production was regularly enhanced in adult bone marrow cells triggered in vitro to clonal growth in the plasma clot culture system.