Background: The concordance of KRAS mutation status between the PT of CRC and synchronous metastases is 95%. However, there were reports showing that KRAS mutation status in metastases may change during chemotherapy (CT). The aim of this study was to evaluate the concordance KRAS, NRAS, BRAF, PIK3CA mutation status between the PT and metachronous metastasesin pts with CRC. Methods: The inclusion criteria were: metachronous metastases (appearance ≥ 12 mo. from the date of surgery for the PT) and ≥ 2 metastasectomy. Only 19 from 1457 (1.3%) pts met the inclusion criteria. PT was located in the colon in 37% pts. The median time between the resection of the PT and metastasectomy was 19.7 mon. (12-63). Most of pts (74%) received CT before metastasectomy. None of the pts received anti-EGFR Mabs. We performed DNA melting analysis with TaqMan probes with following Sanger sequencing for detection of mutation hot-spots in exon 2 and 3 KRAS and NRAS, exon 15 BRAF, exon 9 and 20 PIK3CA. Statistical analyses were performed using SPSS v.22, Inc., Chicago, IL. Results: Mutations in KRAS, NRAS, PIK3CA and BRAF genes in PT were detected in 57.9%, 5.2%, 26.3% and 0%, respectively. Mutations in the tumor material obtained at the first metastasectomy were found in 68.4%, 0%, 21% and 0% pts, respectively. In tumor obtained in subsequent metastasectomy, mutations were detected in 52.6%, 5.2%, 10.5% and 0% pts, respectively. Discordance in any gene mutation status between PT and metastases were found in 42% pts: in KRAS status - 26.3%, NRAS - 5.2% and PIK3CA - 21% pts. The average time between the resection of the PT and metastasectomy did not differ between pts with or without changes in gene status: 18.2 mon. vs. 21.3 mon., p = 0.7. Nonsignificant prevalence in changes of mutation status revealed in pts with rectal cancer: 41.7% vs 14.2%, p = 0.3. CT between resection of the PT and metastasectomy was not associated with changes in gene mutation status (p = 1.0). Conclusions: We detected clinical significant differences in the mutational status of KRAS between the PT and metachronous metastases in pts with CRC. We recommend to re-test of KRAS mutation status in case of metachronous ( ≥ 12 mon.) metastatic disease