Purpose: The epidemiology of colorectal carcinoma is well known to differ among countries but the molecular characteristics are usually assumed to be similar. International differences in molecular pathology have not been studied extensively but have implications for the management of patients in different countries and of immigrant patients. Experimental Design: We evaluated the CpG island methylator phenotype pathway characterized by concordant methylation of gene promoters that often silences transcription of the genes, the microsatellite instability pathway, and K-ras and p53 gene status in 247 colorectal carcinomas from the three selected Middle Eastern countries of Egypt, Jordan, and Turkey. Results: Colorectal carcinoma from Egypt had the lowest frequencies of methylation. In multinomial logistic regression analysis, Jordanian colorectal carcinoma more frequently had methylation involving the p16 tumor suppressor gene (odds ratio, 3.5; 95% confidence interval, 1.2-10.6; P = 0.023) and MINT31 locus (odds ratio, 2.3; 95% confidence interval, 1.0-5.1; P = 0.041). The K-ras proto-oncogene was more frequently mutated in colorectal carcinoma from Turkey (odds ratio, 2.9; 95% confidence interval, 1.2-6.7; P = 0.016), but p53 overexpression was more common in both Jordanian and Turkish colorectal carcinoma than in Egyptian cases (odds ratio, 2.5; 95% confidence interval, 1.2-5.5; P = 0.019; and odds ratio, 3.6; 95% confidence interval, 1.8-7.1; P = 0.0003, respectively). The findings inTurkish colorectal carcinoma were most similar to those reported forWestern cases. Conclusions: Colorectal carcinoma from Middle Eastern countries have differing gene methylation patterns and mutation frequencies that indicate dissimilar molecular pathogenesis, probably reflecting different environmental exposures. These molecular differences could affect prevention strategies, therapeutic efficacy, and transferability of clinical trial results.The epidemiology of colorectal carcinoma in developing countries differs from that of developed countries. Colorectal carcinoma in developing countries, including those in the Middle East, is usually characterized by low incidence, young age of onset, left-sided location, poor differentiation, and paucity of precursor adenomas (1 -9). International studies as well as studies in immigrants suggest that environmental factors, especially lifestyle and dietary differences, play a major part in the observed epidemiologic differences.Morphologic and genetic progression to colorectal carcinoma in an adenoma-adenocarcinoma sequence and in hereditary colorectal carcinoma syndromes are well described (reviewed in ref. 10). Chromosomal instability and mutation of the K-ras proto-oncogene and the p53 suppressor gene are common.