The relevance of the Apc+/Min mouse model in the study of human colorectal cancer remains uncertain due to the predominance of small intestinal adenomas and few, if any, colorectal adenomas. A new strain of Apc+/Min mice (Apc+/Min-FCCC) with significantly greater numbers of colorectal adenomas has been generated and characterized. Male C57BL/6J—Apc+/Min mice (the Jackson Laboratory, Bar Harbor, ME) were crossed with wild-type (Apc+/+) C57BL/6J females from an independent colony at this institution (offspring = Apc+/Min-FCCC) and 233 animals were evaluated over 20 generations. In order to determine the contribution of genetics to the enhanced colorectal adenoma phenotype, breeding pairs (Apc+/Min male × wild type female C57BL/6J) were purchased from the Jackson Laboratory and offspring (Apc+/Min-JAX) were maintained in our facility under identical conditions (n = 98). Animals were fed Purina Rodent chow (#5013) diet containing 5% fat. The entire intestinal tract was examined histopathologically in both strains. Both the Apc and Pla2g2a (candidate for Mom1) genes were sequenced and found to be identical for both the Apc+/Min-FCCC and Apc+/Min-JAX mouse strains. The multiplicity of colorectal adenomas in the Apc+/Min-FCCC mice was much higher than reported in the literature and significantly greater than the multiplicity of colorectal adenomas in Apc+/Min-JAX mice maintained in our facility (P = 0.01). Apc+/Min-FCCC had a significantly greater incidence of rectal prolapse (P = 0.02) and small intestinal adenocarcinomes (P = 0.001), and multiplicity of small intestinal adenocarcinomas (P = 0.001) compared to Apc+/Min-JAX mice. Male Apc+/Min-FCCC mice had significantly greater numbers of colorectal adenomas compared to female Apc+/Min-FCCC mice (P = 0.0002), as did male Apc+/Min-JAX mice vs. female Apc+/Min-JAX mice (P < 0.0001). These results allow us to conclude: (1) Apc+/Min-FCCC mice are unique in that they develop significantly greater numbers of colorectal adenomas and small intestinal cancers, and a significantly greater incidence of small intestinal cancers and rectal prolapse than Apc+/Min-JAX mice. (2) This study represents the first report of a significant gender difference in multiplicity of colorectal adenomas. (3) Differences between Apc+/Min-FCCC and Apc+/Min-JAX mice in currently undefined genetic modifiers may contribute to the enhanced colorectal phenotype. (4) The Apc+/Min-FCCC strain is highly suited for the investigation of colorectal neoplastic disease and chemoprevention studies. © 2005 Wiley-Liss, Inc.