Intracerebroventricular injection of 192 IgG antibody against the p75LNGFR rat low affinity nerve growth factor receptor conjugated with saporin, a ribosome inactivating protein, has been shown to destroy the p75LNGFR-expressing cholinergic neurons of the basal forebrain. We injected this immunotoxin into the hippocampus and studied its retrograde effect upon the cholinergic neurons of the medial septum and the vertical limb of the diagonal band of Broca. Seven days after injection, there was a nearly total depletion of cholinergic axons within the hippocampus. This depletion was associated with a marked and significant decrease in the number of cholinergic neurons of the ipsilateral medial septum and the vertical limb of the diagonal band of Broca. At longer survival times, these changes were more pronounced. Parvalbumin-positive, GABAergic neurons within the same areas of the basal forebrain were not affected by immunotoxin injections. Injections of saporin alone had no effect upon cholinergic neurons. Simultaneous injection of colchicine with the immunotoxin resulted in a significant reduction of retrograde degeneration of cholinergic neurons and relative preservation of hippocampal cholinergic axons. These observations suggest that 192 IgG-saporin is transported retrogradely from the hippocampus to the cholinergic neurons in the medial septum and the vertical limb of the diagonal band of Broca and provide a model for retrograde degeneration of basal forebrain cholinergic neurons following cortically based toxic-pathologic processes.