Dynorphin A(1–17), an opioid peptide that is normally present in the hippocampal mossy fiber system, was localized immunocytochemically in the hippocampal formation of control autopsy and temporal lobe epilepsy (TLE) specimens. In control tissue, dynorphin-like immunoreactive (Dyn- IR) structures were confined to the mossy fiber path and were most highly concentrated in the polymorph (hilar) region of the dentate gyrus. Very few Dyn-IR structures were present in the molecular and granule cell layers of the dentate gyrus. In contrast, in all TLE specimens, Dyn-IR elements were present in these layers. The extent of aberrant staining varied among the TLE specimens, and 2 major patterns were observed. The first was a relatively wide band of reaction product in the inner one-third to one-fourth of the molecular layer (8 cases), and the second was a more limited distribution of immunoreactive fibers and presumptive terminals in the granule cell and immediately adjacent supragranular regions (2 cases). The extent of aberrant Dyn-IR structures appeared to be related to the amount of cell loss in the polymorph and CA3 fields and to dispersion of the granule cell somata. Specimens processed with the Timm's sulfide silver method for heavy metals provided independent evidence for the distribution of mossy fibers. In both control and TLE specimens, the patterns of labeling were virtually identical to those of dynorphin localization. These findings suggest that sprouting of mossy fibers or their axon collaterals has occurred in hippocampal epilepsy and that the reorganized fibers contain at least one of the neuropeptides that are normally present in this system. Such fibers could form recurrent excitatory circuits and contribute to synchronous firing and epileptiform activity, as suggested in studies of experimental models of epilepsy.