Syngeneic mouse islets were transplanted under the renal capsule of athymic nude (nu/nu) C57BL/6 mice. Likewise, neonatal rat islets or fetal porcine islet-like cell clusters (ICC) were transplanted into nude mice. The animals were killed at various times after implantation and the graft-bearing kidney was removed. The transplant was processed for microscopic examination with indirect immunofluorescence for neuropeptides and tyrosine hydroxylase, and with acetylcholine esterase staining to visualize nerve fibers in the graft. In all grafts, reinnervation with both afferent and efferent nerve fibers was encountered 20 weeks after transplantation. The pattern of reinnervation was quantitatively and qualitatively independent of the source of the implanted islets. These findings indicate that the pattern of reinnervation depends on the implantation organ and not on any inherent properties of the implanted endocrine cells. In addition, surviving vasoactive intestinal peptide-positive neurons within the fetal porcine ICC demonstrated an active ingrowth of nerve fibers into the ICC graft and the adjacent kidney parenchyma after transplantation. However, 12 or 16-24 months after transplantation, marked atrophy of all types of nerve fibers in the ICC grafts was observed. The reason for this late degeneration of nerve fibers is unknown, but it may be related to a failure to establish functional neural connections.