Alterations of the downstream effectors of the epidermal growth factor receptor (EGFR) are common events in colorectal cancer (CRC) carcinogenesis. Since EGFR serves as a target for therapy and some downstream effectors of EGFR have predictive and prognostic impact, reliable information on the frequency and concordance of alterations in the signaling pathway has become clinically significant. We, therefore, determined the frequency and coincidence of mutations in the EGFR pathway. We also analyzed the concordance of these alterations between primary tumor and distant metastases. Furthermore, we assessed their prognostic relevance for the development of metastasis. Mutations of KRAS exon 2, BRAF exons 11 and 15, AKT exon 3, and PIK3CA exons 9 and 20 were analyzed by pyrosequencing in 171 primary CRC samples as well as in 63 corresponding metastases. Furthermore, the expression of PTEN and EGFR was assessed by immunohistochemistry. Of the 171 tumors investigated, 60.2 % showed mutations in one or more genes of pathways downstream of EGFR. KRAS exon 2 and BRAF exon 15 mutations were detected in 40.9 and 11.1 % of cases, respectively, and were mutually exclusive. Mutations in exons 9 and 20 of the PIK3CA gene (18.7 %) largely overlapped with exon 2 KRAS mutations (16 of 32 cases; 50.0 %) and, to a lesser extent, with exon 15 mutations of BRAF (2 of 32 cases; 6.3 %). Only one case had simultaneous mutations of AKT exon 3 (0.6 %) and BRAF exon 15. Mutation analysis for KRAS exon 2, BRAF exon 15, PIK3CA exon 20, and AKT exon 3 in primary tumors and in their corresponding metastases revealed 100 % concordance. In one case, a PIK3CA exon 9 mutation in the primary tumor could not be detected in the matched distant metastases (κ = 0.9). Three different scores were applied for the evaluation of EGFR immunohistochemistry, and the range of positive cases varied between 8.8 and 52.6 %. Loss of PTEN expression was detected in 38.6 %. Although the expression of both markers does coincide with KRAS exon 2, BRAF exon 15, AKT exon 3, and PIK3CA exons 9 and 20 mutations, high discordance rates were found. The presence of at least one alteration in downstream effectors of the EGFR pathway was associated with a higher rate of distant metastases (p = 0.002). PIK3CA exons 9 and 20 mutations overlap with KRAS exon 2 and BRAF exon 15 mutations, and BRAF exon 15 and AKT exon 3 mutations co-occur in a single tumor, whereas KRAS exon 2 and BRAF exon 15 mutations are mutually exclusive. This suggests that mutations in the PIK3CA/PTEN/AKT branch of the EGFR pathway are less important than those of the RAS/RAF/MAPK branch for the progression of CRC. We found no difference in the mutational status of KRAS exon 2, BRAF exon 15, and AKT exon 3 between primary tumor and distant metastasis, validating both for diagnostic purposes. PIK3CA exons 9 and 20 mutations can be discordant between primary tumor and distant metastasis, and therefore, the lesion which is targeted for therapy should be tested. Protein expression of PTEN and EGFR using current protocols yields highly discordant results, and better standardization is needed before these markers can be used for diagnostic purposes.