Plasma is the most widely collected biofluid and an invaluable source of biomarkers. The analysis of plasma using discovery mass spectrometry–based proteomics faces challenges as the 22 most abundant proteins constitute more than 99% of the total protein content. This is hindering the detection of lower abundant proteins, potentially disease-relevant biomarkers. To overcome this, we developed and optimized an enrichment workflow, termed P2 Plasma Enrichment System, based on protein corona formation. Protein corona formation leads to a reduction in dynamic range enabling the detection of lower abundant proteins. We characterized P2 in terms of robustness quantitative precision and quantitative accuracy with acquisition throughputs ranging from 40 to 500 samples per day.