The astrocyte mitogenic activity of normal and injured rat brain extracts was greatly enhanced by antibodies to epidermal growth factor receptor (EGFR). The antibodies appear to act by removing from the extracts inhibitory molecules immunologically related to EGFR. Three molecular species recognized by anti-EGFR antibody in brain extracts (molecular weights 41, 52, and 69 kilodaltons) did not seem to originate from EGFR proteolysis. The increase in astrocyte mitogenic activity in brain tissue following injury correlated with a reduction in the levels of soluble EFGR-cross-reacting material and a decrease in mitogen inhibitory activity. The decrease in EGFR-related mitogen inhibitor also correlated with a large increase in astrocyte membrane EGFR immunoreactivity, and intracerebral injection of antibodies to EGFR caused the appearance at the injection site of numerous EGFR-positive reactive astrocytes. Invasion of brain tissue by EGF/EGFR-related blood components may be the signal that initiates astrocyte activation. EGFR-related immunoreactive molecules are also present in extracts of other tissues and may have a general role in the control of cell division.