Updated project metadata. Clinical misdiagnosis between cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) affects treatment plans and carries risks of potential for recurrence, metastases, morbidity and mortality. We report the development of a novel tissue sampling approach with molecular biopsy using electroporation. This method, coined e-biopsy, enables non-destructive non-thermal permeabilization of cells in the skin for efficient vacuum-assisted extraction of informative biomolecules for rapid diagnosis. We used e-biopsy for ex vivo proteome extraction from 3 locations per patient in 21 cSCC and 20 BCC pathologically validated human tissue samples. The total 123 extracted proteomes were profiled using LC/MS/MS. The obtained mass spectra presented significantly different proteome profiles for cSCC and BCC with several hundreds of proteins significantly differentially expressed in each tumor in comparison to the other. Notably, our study showed that proteomes sampled with e-biopsy from cSCC and BCC lesions are different, and that 7 proteins were significantly overexpressed in BCC in comparison to cSCC even after the Bonferroni correction (FDR=7.1e-03). Our results provide evidence that the e-biopsy approach could potentially be used as a tool to support cutaneous tumors classification with rapid molecular profiling.