This study compares the efficacy of porcine intestinal submucosa (SIS) patch graft versus SIS-tube graft in esophageal replacement, using a novel esophageal regeneration model. Clinical function, as well as macroscopic and microscopic morphology were evaluated in both SIS-treated groups. We performed semi-circumferential esophageal excision followed by repair of the defect using either a SIS-patch graft (group I) or segmental esophageal excision followed by a SIS-tube interposition graft (group II) in rats. The 28-day survival rate was significantly different between the SIS-treated groups (100% in group I vs. 0% in group II). Unlike the rats in group II, which died within the first postoperative month due to esophageal dysfunction, all surviving animals in group I resumed a normal solid diet within a few days after surgery, without signs of esophageal dysfunction and gained weight. Barium swallow studies showed no evidence of fistula, significant stenosis or diverticula. No hematological or serum biochemistry abnormalities were found. By day 150 the SIS patch was replaced by esophageal-derived tissues. In the rat model, a patch graft technique using SIS appeared to induce esophageal regrowth and provided an initial and long-term satisfactory function, while a tube-shaped graft technique using SIS was unsuccessful.