Background Squamous cell lung cancer (SCLC) arises from bronchial changes: basal cell hyperplasia (BCH), squamous metaplasia (SM), and dysplasia. However, the premalignant process preceding SCLC is not inevitable; it can stop at any of the bronchial lesions. Previously, we hypothesized that combinations of premalignant lesions observed in the small bronchi of SCLC patients can reflect the different “scenarios” of the premalignant process: BCH i —the stoppage at the stage of hyperplasia and BCH SM —the progression of hyperplasia to metaplasia. Methods and Results In this study, using whole-genome bisulfite sequencing we analyzed the DNA methylome of two forms of BCH: isolated BCH (BCH i ) and BCH co-occurred with SM (BCH SM ) in the small bronchi of SCLC patients. It was shown that BCH i harbored differentially methylated regions (DMRs) affecting genes associated with regulating phosphatase activity. In BCH SM , DMRs were found in genes involved in PI3K-Akt and AMPK signaling pathways. DMRs were also found to affect specific miRNA genes: miR-34a and miR-3648 in BCH i and miR-924 and miR-100 in BCH SM . Conclusions Thus, this study demonstrated the significant changes in DNA methylome between the isolated BCH and BCH combined with SM. The identified epigenetic alterations may underlie different “scenarios” of the premalignant process in the bronchial epithelium.