The systems-level relationship between the proteomes of cerebrospinal fluid (CSF) and plasma has not been comprehensively described so far. Recently developed shotgun proteomic workflows allow for deeper characterization of the proteomes from body fluids in much larger sample size. We deployed state-of-the-art mass spectrometry-based proteomics in paired CSF and plasma samples volunteered by 120 elders with and without cognitive impairment to comprehensively characterize and examine compartmental proteome differences and relationships between both body fluids. We further assessed the influence of blood-brain barrier (BBB) integrity and tested the hypothesis that BBB breakdown can be identified from CSF and plasma proteome alterations in nondemented elders. We quantified 790 proteins in CSF and 422 proteins in plasma, and 255 of the proteins were identified in both compartments. Pearson's statistics determined 28 proteins with associated levels between CSF and plasma. BBB integrity as defined with the CSF/serum albumin index influenced 76 CSF/plasma protein ratios. In least absolute shrinkage and selection operator models, CSF and plasma proteins improved identification of BBB impairment. In conclusion, we provide here a first comprehensive draft map of interacting human CSF and plasma proteomes, in view of their complex and dynamic compositions, and influence of the BBB.