Sympathetic neurons from the peripheral nervous system invade the hippocampus following destruction of its septal inputs. It is thought that sympathetic ingrowth is due to the loss of cholinergic innervation since damage to the medial septum-diagonal band complex (MSDB) or its major efferent bundle, the fimbria-fornix, is required to induce ingrowth. The MSDB provides the major source of cholinergic fibers projecting to the hippocampus; however, non-cholinergic (e.g. GABAergic) neurons are also present in the MSDB and project to the hippocampus. Thus, the role of cholinergic denervation in sympatho-hippocampal sprouting cannot be directly tested by non-specific lesion techniques. In the present study, colchicine, which has been demonstrated to be specifically toxic to cholinergic neurons in the medial septum, was injected into each lateral ventricle of female Sprague-Dawley rats. Following colchicine-induced degeneration of cholinergic septohippocampal neurons, coarse, branched fibers immunoreactive for dopamine-beta-hydroxylase were observed predominantly in the dentate gyrus, on both sides of the granule cell layer, with increasing density as survival time increased. These results support the hypothesis that the invasion of the hippocampal formation by sympathetic fibers results from cholinergic denervation.