Here, we have reported the plasma proteomes of 6 malignant melanoma (MM) and 6 lung adenocarcinoma (LUAD) patients, generated using HiRIEF pre-fractionation and tandem mass tags (TMT)-based peptide quantification. We have detected traditional plasma marker proteins, as well as many LUAD and MM related proteins in the cancer plasma. Our advanced proteomics workflow exhibits high proteome coverage for both plasma and plasma derived extracellular vesicles (pEVs), providing the ability to detect potential disease-specific markers in pEVs enriched from clinical plasma samples.