Useful morphologic criteria for frozen section diagnosis of pancreatic and periampullary carcinoma were established by prospective review of 64 frozen sections in this region, with permanent section correlation and patient follow-up. These were divided into three major and five minor criteria based on frequency of occurrence and reproducibility. Major criteria were: 1) nuclear size variation of 4:1 or greater between ductal epithelial cells, 2) incomplete ductal lumens, and 3) disorganized duct distribution. Minor criteria, less frequently and reproducibly observed but valuable diagnostic aids, included: 1) huge, irregular epithelial nucleoli; 2) necrotic glandular debris; 3) glandular mitoses; 4) glands unaccompanied by connective tissue stroma within smooth muscle bundles (periampullary biopsies); and 5) perineural invasion. Combined application of both major and minor criteria is especially helpful in cases complicated by chronic pancreatitis.