Epidermal growth factor (EGF) induces the degradation of EGF receptors in both human foreskin fibroblasts and A-431 cells. Similar degradation products of 125I-EGF covalently linked to its receptor appeared at the same times in both A-431 cells and fibroblasts when the cells were exposed to a concentration of 10 ng/ml EGF. Although the products between the two cell types differed in molecular weight, this was at least partly caused by an actual difference in the receptor proteins from the two cell types (as shown by partial proteolysis) rather than from different pathways of receptor degradation. However, when EGF receptors were biosynthetically labeled, no receptor degradation products could be observed, even when the receptor was labeled with radioactive mannose or phosphate, molecules which would predominantly label the outside or inside face of the receptor, respectively. At 20 degrees C, degradation of the receptor slowed and a 150,000-dalton degradation product was observed. This degradation product has previously been observed in cell homogenates produced in the presence of calcium, mediated by calpain. Thus, calpain may play a role in the intracellular degradation of the EGF receptor.