We examined the extent to which regional lymph nodes may be dissected while preserving the superior mesenteric nerve plexus (PLsma) in radical surgery for periampullary cancer. The lymph nodes were distributed uniformly on the right and left hemicircles of the superior mesenteric artery (SMA) and along its longitudinal axis. Of a total of 142 lymph nodes, 134 (94.4%) were located outside the PLsma. Dissection of the superior mesenteric lymph nodes is theoretically to be possible while preserving the superior mesenteric nerve plexus. We further investigated neural invasion and nodal involvement in the resected specimens with periampullary cancer. The following surgical approaches to lymph nodes and nerve plexus around the SMA were found best based on the results obtained. In pancreatoduodenectomy for ampullary cancer superior mesenteric lymph nodes must be dissected circumferentially, and additional dissection of right hemicircle of the PLsma is advisable. Invasive pancreatic cancer should be treated by extensive resection including complete dissection of the PLsma. This, however, leads to intractable diarrhea and digestive malabsorption. Complete dissection of the superior mesenteric nodes, right hemicirclar dissection of the PLsma and intraoperative radiation therapy are thus recommended. In mucin-producing pancreatic cancer, dissection of the PLsma is not necessary.