Background:  Smad4 is vital to the roles of Smads 2 and 3 in transforming growth factor‐beta (TGF)‐β signal transduction, and inactivated Smad4 is common to human gastrointestinal cancers. The embryonic liver fodrin (ELF) is a β‐spectrin that facilitates the nuclear translocation of activated Smad4.Methods:  Smad4 +/− mice, known to develop gastrointestinal cancer, were crossbred with elf+/− mice. The smad4+/− and smad4+/−/elf+/− offspring were autopsied as abnormalities developed.Results:  In addition to polyps and adenocarcinomas of the stomach and duodenum, the smad4+/− mice developed squamous cell carcinomas of the skin, oral mucosa and forestomach, benign neoplasms of connective tissue and lacrimal gland, and a lymphoma. The smad4+/−/elf+/− mice developed extensive hyperplasia and neoplasia of the gastric mucosa.Conclusion:  These findings indicate that investigating interactions among smad4, elf, and other genes involved in TGF‐β signaling should be useful in further delineating the processes of neoplasia in a wide variety of tissues.