DNA methylation plays a significant role in assuring cell identity, thus potentiating its application in molecular classification of cancers in respect to tissue-origins or clinically and etiologically distinct subtypes. In this study, we optimized our liquid hybridization capture-based bisulfite sequencing (LHC-BS) approach on the gene promoter regions of 11 cell lines. Our results indicated that promoter methylomes could not only cluster cancer cell lines with respect to tissue origins but also differentiate cancer subtypes based on CpG island methylator phenotype (CIMP). Promoter-targeted LHC-BS as means for comprehensive screening and classifying cancer cells with promoter methylomes provided a powerful strategy for further complex clinical studies.