One hundred and forty colonic adenocarcinomas originating on the left side of the colorectum and 70 colorectal carcinomas originating on right side of the colorectum were examined for activating mutations of codons 12 and 13 of the C-KI-RAS proto-oncogene. Rates of mutation were significantly different (right colon 43%, 30/70 versus left colon 23%, 32/140; P = 0.0025). Adenocarcinomas from the left side of the colorectum showed a significant association between C-KI-RAS activation and tumour progression, including the presence of distant organ metastasis at the time of surgery (P = 0.0039), and during patient follow-up (P = 0.00027), whereas those from the right of the colorectum did not (P = 0.4 and P = 0.5, respectively). Mutation of the C-KI-RAS proto-oncogene was found to be associated with a significantly poorer patient prognosis on the left of the colorectum (P = 0.0001 by log rank analysis of Kaplan-Meier plots) but not on the right (P = 0.7). These results demonstrate that, not only is the timing and frequency of C-KI-RAS activation different between carcinomas originating on the left or right of the colorectum, but also that the biological consequences of such mutations may differ.