Despite improvements in screening for early diagnosis and treatment, colorectal cancer (CRC) remains a common disease with significant mortality worldwide, in both males and females. Among the treatment modalities, radiotherapy has an established therapeutic role, providing local control of the advanced disease. However, many patients experience resistance to radiotherapy. Therefore, understanding the mechanisms involved in radiotherapy resistance is an important approach to achieve high therapeutic efficacy. This work explored the role of fibroblast growth factor receptor 4 (FGFR4), a member of the FGFR family that is frequently upregulated in colorectal cancer, as a candidate target mediating radioresistance of CRC. The result of this study showed that similar to knockdown of the repair protein RAD51, silencing of FGFR4 resulted in significant decrease in the long-term surviving cell fraction in the radioresistant HT29. In the radiosensitive colorectal cancer cells, increased FGFR4 expression was found to exclusively enhance the survival of the mismatch proficient SW480 cells but not the mismatch deficient DLD1 cells. The FGFR4-mediated survival effects found to be induced mainly through stabilizing RAD51-mediated homologous recombination pathway (HR). DLD1 cell cannot profit from this, as HR is mitigated by the loss of mismatch repair proteins. In addition, differences between the low FGFR4-expressing DLD1 and SW480 cells were observed, including regulation of anti-apoptotic proteins and cell cycle arrest phases. Specifically, the resistance of DLD1 to radiation was found to be mediated through upregulation of the anti-apoptotic protein, survivin, and not via RAD51 or any of the four FGF receptors. However showing no impact on the radiation-survival of DLD1 cells, the increased expression of FGFR4 significantly enhanced the proliferation, migration and invasion properties of these cells. In addition, forced expression of FGFR4-388Gly but not FGFR4-388Arg in DLD1 cells significantly enhanced tumor growth in SCID mouse model. Clinically, high expression of FGFR4 in biopsy specimens derived from neoadjuvant chemoradiation-treated rectal cancer patients was found to be significantly correlated with a poor response. In addition, the scoring intensity of FGFR4 shown to be significantly higher in partially and non-responsive patients as compared to the ones who completely responded to neoadjuvant chemoradiation. In tumor specimen obtained from non-responsive patients FGFR4 was co-expressed with RAD51. In conclusion, FGFR4 overexpression may predict neoadjuvant radiotherapy response, serving as a mean to select CRC patients who could potentially benefit from neoadjuvant radiotherapy.