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Purpose  To investigate the correlation between chemoresistance of colorectal cancer to 5-fluorouracil and BNIP3 and the underlying mechanism.  Methods  BNIP3 protein in specimens was evaluated using immunohistochemistry. Semi-quantitative reverse transcription PCR and Western blot was employed to assay gene expression. The promoter methylation status of BNIP3 was examined by methylation-specific PCR. Drug sensitivity was assayed using MTT assay.  Results  Specimens from 81 patients with colorectal cancer receiving 5-fluorouracil-based chemotherapy were analyzed. BNIP3 expression was negative in 42 cancer samples. The mean score of BNIP3 in cancer was 1.8±0.2 and it was 3.7±0.5 in adjacent colorectum ( p &lt;0.05). The response rate of the BNIP3 positive group was 63.6% and that of the negative group was 36.4% ( p =0.021). The median PFS of the BNIP3 positive group was 9.25 months and that of the BNIP3 negative group was 6.5 months ( p =0.011). BNIP3 mRNA was not detectable in 4 of 8 colorectal cell lines and all these 4 cell lines displayed BNIP3 methylated allele only. Other 4 cell lines what expressed detectable BNIP3 displayed BNIP3 unmethylated allele only or both unmethylated and methylated alleles. 5-Aza dramatically increased BNIP3 expression. Knockdown of DNMT1 increased BNIP3. Knockdown of DNMT3B alone did not detectably change BNIP3 expression while knockdown of both DNMT1 and DNMT3B increased BNIP3 expression more than knockdown of DNMT1 alone. Knockdown of BNIP3 decreased chemosensitivity to 5-fluorouracil and increasing BNIP3 through demethylation increased chemosensitivity.  Conclusion  Chemoresistance of colorectal cancer to 5-fluorouracil is associated with silencing of the BNIP3 gene through aberrant methylation via DNMT1/DNMT3B.