Background: Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens, and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4 and MyD88 mediated signalling to orchestrate downstream inflammatory responses. While MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Methods: Colitis was induced in wild type (WT) and Mal-deficient (Mal^-/-) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total-body gamma irradiation followed by transplantation of bone marrow cells. Results: In the DSS model of colon epithelial injury, Mal^-/- mice developed increased inflammation and severity of colitis relative to WT mice. Mal^-/- mice demonstrated the presence of inflammatory cell infiltrates, increased crypt proliferation, and presence of neo-formations. Furthermore, in the AOM/DSS model, Mal^-/- mice had greater incidence of tumours. Mal^-/- and WT bone marrow chimeras demonstrated that non-haematopoietic cell expression of Mal had an important protective role in the control of intestinal inflammation and inflammation-associated cancer. Conclusions: Mal is essential for the maintenance of intestinal homeostasis and expression of Mal in non-haematopoietic cells prevents chronic intestinal inflammation that may predispose to colon neoplasia.