A defect in heme synthesis is well documented to occur in lead intoxication. Globin synthesis and the alpha/beta globin chain synthesis ratio have been shown to be disturbed in lead poisoning. To elucidate further the nature of the inhibitory effect of lead on hemoglobin synthesis, reticulocyte-rich peripheral blood samples have been incubated with lead at concentrations of 10(-6), 10(-5), and 10(-4) M, equivalent to 20, 200, and 2,000 mug/dl (.96, 9.6 and 96.0 mumol/l), respectively. The incorporation of tritiated leucine into globin was determined. Globin chain synthesis decreased to 85, 49 and 15% of the control value with increasing lead concentrations. The effect of heme on inhibition of globin synthesis by lead was studied by incubating reticulocyte-enriched blood with lead 10(-5) M (200 mug/dl; 9.6 mumol/l) in the presence or absence of heme at a concentration of 10(-3) M. Lead alone depressed the incorporation of tritiated leucine to 45% of control, while globin synthesis with heme alone was 109% of control. Although in the presence of both heme and lead, the mean incorporation of leucine into globin was 69.2% of control, the increase was not significantly different from that obtained with lead alone. It is concluded that (1) lead has an inhibitory effect on globin synthesis at a concentration considered to be within the acceptable range encountered in environmental lead pollution, and the extent of inhibition is dose-dependent; (2) the effect of lead on globin synthesis is not significantly prevented by heme and, therefore, does not appear to be mediated through the well-documented inhibitory effect of lead on heme synthesis.