Our previous study revealed that alginate gel cross-linked with covalent bonds promoted peripheral nerve regeneration in the cat and rat. The present study analyzed nerve regeneration through alginate gel in the early stages within 2 weeks and the late stages up to 21 months after implantation. The alginate is natural acidic polysaccharides. Ethylenediamine and EDC were well dissolved in 1% sodium alginate aqueous solution, resulting in a transparent gel cross-linked with covalent bonds. The gel was washed, freeze-dried, and sterilized by g-irradiation. Rat sciatic nerve was cut, and 10-mm gap was made. Two pieces of alginate gel were implanted into the gap. The suture operation to the nerve tissue was not done. The collagen sponge and the fibrin glue were implanted as a control material. A left sciatic nerve of the untreated was used as a normal control. The animals were transcardinally perfused with fixative in phosphate buffer. After perfusion, the sciatic nerve segment including the implanted alginate gel was dissected out. Double-labeling immunohistochemical staining of longitudinal sections was performed by using the specific antibodies anti-S100 antibody for Schwann cells and anti-b-tubulin class III antibody for regenerated axons, respectively. Ultrathin sections were cut transversely, stained with lead citrate and uranyl acetate, and observed by transmission electron microscopy. Four days after surgery, regenerating axons grew without Schwann cell investment through the partially degraded alginate gel, being in direct contact with the alginate without a basal lamina covering. Numerous mast cells infiltrated into the alginate. One to 2 weeks after surgery, regenerating axons were surrounded by common Schwann cells to form small bundles, with some axons at the periphery being partly in direct contact with alginate. At the distal stump, numerous Schwann cells had migrated into the alginate 8-14 days after surgery. They had no basal laminae. The diameter of regenerated myelinated fibers was small (approximately 1 µm) at 8 weeks, but increased in diameter, having a distribution pattern similar to that of normal nerve 21 months after surgery. Much better nerve regeneration was found in alginate gel-, than collagen sponge-, and fibrin glue-implanted distal stump 12 months after surgery. These results indicate that alginate gel has good biocompatibility for regenerating axon outgrowth and Schwann cell migration, and that regenerated fibers can have a diameter as thick as that of normal fibers in the long term. Alginate gel is a promising material for use as an implant for peripheral nerve regeneration.