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KRASgenotyping is mandatory before anti-epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer, which is the second leading cause of cancer-related death in the United States and in Europe. Thus, large-scale KRASmutation screening is needed for efficient patient management and in the future metastatic colorectal cancer genotyping might also include the detection of the BRAFV600E mutation, which is a very strong negative prognostic factor in colorectal cancer. We report our experience of routine KRAS/BRAFmutation screening practice performed on 1130 formalin-fixed paraffin-embedded tumor samples from 992 colorectal cancer patients. DNA was extracted from macrodissected tumor areas highlighted by a pathologist, KRAScodons 12/13 and BRAFV600E mutations were assessed in a single SNaPshot® multiplex assay and each mutation was confirmed by an independent analysis. KRASand BRAFmutations were, respectively, present in 41.8 and 6.5% of the tumor samples. If KRASand BRAFmutations were mutually exclusive, four samples presented two concomitant KRASmutations. Genotyping of paired primary tumors and metastases from 44 patients indicated that 5 patients (11.4%) presented discordant KRASmutational status. KRASgenotype heterogeneity was also observed within primary tumor sites in seven cases. Non-reproducible KRASartefactual mutations were detected in 53 samples (4.7%). We found that the prominent mechanism leading to these artefactual mutations was the fragmentation of DNA occurring during tissue processing. Routine KRASgenotyping performed on formalin-fixed paraffin-embedded tissues requires, therefore, the development of quality control scheme for molecular pathology, especially because of DNA damages induced by formalin fixation. The tumor heterogeneity observed in some patients indicates that it should be more appropriate to perform KRASgenotyping on metastases if sample is available.