To investigate the response of selected sympathetic ganglia to experimental injury, neonatal rat pups were treated with either 6-hydroxydopamine (6-OHDA), guanethidine, or antiserum to nerve growth factor (anti-NGF). When examined at one month of age, each of the treatments resulted in a significantly greater loss of neurons and tyrosine hydroxylase activity in paravertebral (superior cervical and stellate) versus prevertebral (superior mesenteric and celiac) sympathetic ganglia. Guanethidine treatment produced the largest differential in neuron loss and tyrosine hydroxylase activity between pre- and paravertebral ganglia. Histologically, the acute phase of guanethidine-induced injury in the superior cervical, paravertebral, ganglia was characterized by a prominent mononuclear cell infiltrate and extensive neuronal degeneration. Minimal histopathologic changes were seen in the superior mesenteric, prevertebral, ganglia of the same animals. Immunolocalization of tyrosine hydroxylase and neuropeptide Y (NPY) in guanethidine-treated animals showed a preferential loss of sympathetic innervation of the extramural mesenteric vasculature with relative sparing of the noradrenergic innervation of Auerbach's myenteric plexus. Differences in the susceptibility of sympathetic ganglia to various insults may underlie the selective and heterogeneous involvement of sympathetic ganglia in clinical and experimental situations.