Recent studies suggest that long-interspersed nucleotide element-1 ( ) hypomethylation is commonly found in colorectal cancer (CRC), and is associated with worse prognosis. However, the utility of methylation on the prognosis of CRC is still controversial, and may be due to the fact that some clinical and pathological features may affect methylation. Thus, the aim of this study was to assess the prognostic value of tumor methylation in CRC, through their association with the CRC clinical and pathological characteristics. Survival of sixty-seven CRC patients was evaluated according to the median of tumor methylation, as well as pathological and oncological variables. We also studied the association between methylation and pathological features, and finally, we assessed the overall and disease-free survival of methylation, stratified by neoadjuvant treatment and further checked by multivariate Cox regression to assess the statistical interactions. was hypomethylated in the CRC tumor with respect to the tumor adjacent-free area ( < 0.05), without association with any other clinical and oncological features, nor with overall and disease-free survival rates for CRC. Relevantly, in neoadjuvant treatment, methylation was associated with survival rates. Thus, disease-free and overall survival rates of treated CRC patients were worse in the hypomethylated tumors than those with normal methylation ( = 0.004 and 0.0049, respectively). Indeed, was hypermethylated more in the treated patients than in the non-treated patients ( < 0.05). The present study showed that tumor hypomethylation was associated with worse survival rates in only treated patients. Our data suggest an interactive effect of neoadjuvant treatment and tumor methylation, which could be a specific-tissue biomarker to predict survival of the treated patients, and help to personalize treatment in CRC.