In the rabbit reticulocyte cell-free system, optimal globin synthesis is dependent upon an adequate level of heme. The effect of heme is mediated by an inhibitor of globin synthesis initiation termed HCR. In addition to marked inhibition of total globin synthesis, HCR results in a decreased alpha/beta globulin synthesis ratio. We describe here the use of INH as a relatively nontoxic inhibitor of heme synthesis in intact rabbit reticulocytes with a resultant inhibition of globin synthesis. In parallel with the inhibition of globin synthesis in reticulocytes, an inhibitor of globin synthesis in the hemin-supplemented cell-free system is generated. No INH-induced alterations in alpha/beta synthesis ratio could be found in "stress" reticulocytes from phenylhydrazine-treated rabbits, but "normal" reticulocytes from untreated rabbits showed a decreased alpha/beta ratio. Inhibition of heme synthesis and the resulting decrease in globin synthesis and intracellular hemoglobin concentration may have application as a potential treatment of homozygous sickle cell disease.