Colloid carcinomas of organs such as the breast, colon, and prostate have been well characterized. However, up until now there have been only a few studies of colloid carcinomas of the pancreas and periampullary region, and the number of colloid carcinomas in these studies has been limited. A search of our files revealed 39 resections for pancreatic and periampullary carcinomas with colloid differentiation. All neoplasms were extensively sampled. "Carcinomas with colloid differentiation" were defined as tumors associated with abundant extracellular mucin containing free-floating mucinous epithelial cells. Cases with >50% colloid differentiation were classified as "colloid carcinomas," whereas those with less were termed "carcinomas with focal colloid features." Cases with no colloid differentiation at all were designated "carcinomas without colloid differentiation." Of the 39 carcinomas, 31 were colloid carcinomas, and eight were carcinomas with focal colloid features. Twenty-seven were centered in the pancreas, seven were in the duodenum, and five were in the ampulla of Vater. Remarkably, 38 of the 39 carcinomas (97%) arose in association with an intraductal papillary mucinous neoplasm or a tubular/tubulovillous adenoma. Of the patients with colloid carcinomas, the 2-and 5-year actuarial survival rates were 69% and 29%, respectively. There was no significant difference in survival rates between patients with colloid carcinomas and patients with adenocarcinomas without colloid differentiation, whether or not the latter arose in association with intraductal papillary mucinous neoplasms or tubular/tubulovillous adenomas. In a multivariate model colloid differentiation was not an independent predictor of patient survival, while other factors such as tumor location, perineural invasion, vascular invasion, and margin status after resection independently influenced patient survival. Most colloid carcinomas of the pancreas and periampullary region arise in association with a well-defined in situ papillary neoplasm. The diagnosis of a pancreatic or periampullary colloid carcinoma should encourage the pathologist to search for an associated low-grade in situ component. In addition, colloid carcinomas of the pancreas and periampullary region do not necessarily have a better prognosis than carcinomas without colloid differentiation. Instead, other factors such as tumor location, perineural invasion, vascular invasion, and margin status after resection are far more important.