Treatments with monoclonal antibodies targeting the epidermal growth factor receptors (EGFR) have improved the prognosis of metastatic colorectal cancer (CRC). Mutated KRAS status is predictive of resistance to anti-EGFR agents and allows the selection of KRAS wild-type patients who may benefit from these targeted therapies. We report an original case of metastatic CRC including three synchronous primary tumors with three different KRAS statuses. We discuss the possible therapeutic impact of this clinical case and the role of multiple samplings for KRAS status determination.