Colorectal cancers (CRC) among Israeli Arabs differ from those diagnosed in Jewish Israeli individuals in two manners: an earlier age of occurrence and a low frequency. These differences are unaccounted for and thus prompted us to perform genetic analysis in Israeli Arab CRC patients. Analysis included the major Hereditary non-polyposis colorectal cancer (HNPCC) genes and the APC I1307K mutation (MIM# 175100.0029). Twenty-five patients and 25 relatives from 24 unrelated families were clinically classified according to personal and familial cancer history. If MSI (microsatellite instability) was displayed in tumor tissue, patients underwent mutation analysis of the MSH2 and MLH1 genes using DGGE (denaturing gradient gel electrophoresis) and sequencing. MSI was detected in 9/21 of the tumors tested (43%). Two novel missense mutations were diagnosed among 11 fully analyzed patients: a change of A to G at position 380 in MSH2 (N127S), and a D601G mutation in MLH1. The I1307K mutation was detected in 8 families (8/24, 33.3%). This is the first report of genetic analysis in familial CRC associated genes among Israeli Arabs. We suggest that the I1307K mutation may contribute to CRC in Israeli Arabs and that inactivating mutations of MSH2 and MLH1 may not be a major cause for early onset CRC.