One of the hallmarks of the hyperglycemic-hyperinsulinemic infant of the diabetic mother (IDM) is macrosomia and selective organomegaly. Primary hyperinsulinemia, with insulin levels similar to those observed in human IDMs at delivery, was produced in the fetal rhesus monkey during the last third of gestation. The effects of this physiologically relevant hyperinsulinemia, in the absence of hyperglycemia, on fetal growth were studied. Fetal macrosomia, with a 23% increase in total body weight, was observed in physiologically hyperinsulinemic fetuses. A similar 27% increase in weight was produced by fetal insulin levels that were 10 times higher. A logarithmic correlation was observed between fetal birth weight ratio and fetal plasma insulin concentration. In contrast to this increase in weight, skeletal growth, as measured by crown-heel length and head circumference, was not affected by hyperinsulinemia. Only cardiomegaly was found in the low-dose hyperinsulinemic fetuses, whereas cardiomegaly, hepatomegaly, and splenomegaly were produced by hyperinsulinemia in which insulin levels were in the highest range. Compositional analysis of heart and skeletal muscle indicated no differences in the protein, RNA and DNA concentration, or in the protein-to-DNA ratio in hyperinsulinemic fetuses. We interpret these data as indicating that fetal insulin plays the predominant role in controlling the normal, as well as the augmented, fetal weight characteristic of the human infant of the diabetic mother.