Heart failure (HF) is a leading cause of death worldwide. While early detection is vital for prevention of this cardiovascular disease, understanding molecular mechanisms pertaining to HF is urgent for developing effective therapies. Complementary to imaging and genetic information, discovery of novel plasma markers will provide insight into early diagnosis and prognosis of HF and new HF therapeutics. Here we seek to identify such protein markers using advanced mass spectrometry (MS)-based discovery proteomics, one of the forefront enabling technologies for unbiased identification of plasma protein markers. Our aim was to identify protein biomarkers that are not only useful in diagnostics, but also helpful in prediction of therapeutic targets. To this end, we pursued isolation of plasma extracellular vesicles (EVs) followed by MS-based quantitative proteomics (EVproteomics) with the hypothesis that EVs are rich in biomarkers with biological importance and reduced in highly abundant proteins such as albumin that interfere with the detection of low abundant proteins by MS. Our EVproteomics allowed identification of over 900 distinct proteins in the plasma EVs with less than 15% of the highly abundant plasma proteins in comparison to the results obtained through classical depletion approaches. With this motivation, we carried out quantification of EVproteome of plasma from HF patients against normal controls using tandem mass tag (TMT) labelling-based proteomics. Analysis of the results showed a distinct cluster segregating the control and disease cohort that contains the reported proteins as potential cardiovascular disease markers, and new markers as well. This promising result, in its validation phase, has reflected the merit of EVproteomics in HF circulating biomarkers discovery.