There is extensive evidence that protein synthesis in reticulocyte lysates is inhibited during haem deficiency because of phosphorylation of initiation factor eIF-2 by a protein kinase (the haem-controlled represser, HCR)1–5. Other protein kinases, which are activated by low concentrations of double-stranded RNA, have also been identified in reticulocytes1,6 and in extracts from interferon-treated cells7–10, and these phosphorylate an identical site on eIF-2 11–12. Despite the extensive documentation of such enzymes, however, the precise mechanism of inhibition has remained unclear, mainly because phosphorylation fails to affect many partial reactions of polypeptide chain initiation13,14. We present here evidence that the exchange of GTP for GDP bound to eIF-2 is inhibited following phosphorylation of the factor. Such an effect may inactivate eIF-2 by impairing the ability to recycle between successive rounds of protein synthesis.