Colorectal cancers remain to be a common cause of cancer-related death. Early-onset cases as well as those ofvarious ethnic origins have aggressive clinical features, the basis of which requires further exploration. The aimof this work was to examine the expression patterns of p15INK4b and SMAD4 in colorectal carcinoma of differentethnic origins. Fifty-five sporadic colorectal carcinoma of Egyptian origin, 25 of which were early onset, and54 cancers of Finnish origin were immunohistochemically stained with antibodies against p15INK4b and SMAD4proteins. Data were compared to the methylation status of the p15INK4b gene promotor. p15INK4b was totally lostor deficient (lost in ≥50% of tumor cell) in 47/55 (85%) tumors of Egyptian origin as compared to 6/50 (12%)tumors of Finnish origin (p=7e-15). In the Egyptian cases with p15INK4b loss and available p15INK4b promotormethylation status, 89% of cases which lost p15INK4b expression were associated with p15INK4b gene promotorhypermethylation. SMAD4 was lost or deficient in 25/54 (46%) tumors of Egyptian origin and 28/48 (58%)tumors of Finnish origin. 22/54 (41%) Egyptian tumors showed combined loss/deficiency of both p15INK4b andSMAD4, while p15INK4b was selectively lost/deficient with positive SMAD4 expression in 24/54 (44%) tumors.Loss of p15INK4b was associated with older age at presentation (>50 years) in the Egyptian tumors (p=0.04). Thesedata show for the first time that p15INK4b loss of expression marks a subset of colorectal cancers and ethnic originmay play a role in this selection. In a substantial number of cases, the loss was independent of SMAD4 butrather associated with p15INK4b gene promotor hypermethylation and old age which could be related to differentenvironmental exposures.