Protein-protein interactions (PPIs) play a critical role in virtually all cellular processes. Their context-dependent characterization is thus a key objective of proteomic research. We and others have previously shown that chromatographic fractionation of native protein complexes (e.g. through size-exclusion chromatography, SEC) can be effectively combined with high-throughput, bottom-up mass-spectrometry-based proteomics (e.g. data-independent acquisition-based SWATH-MS), to support proteome-wide characterization of protein complexes.To enable qualitative and quantitative comparison of the proteome organization encoded in these datasets, across multiple experimental conditions, scalable and robust 1/32 analysis strategies are required. To address this need, we developed the Size-Exclusion Chromatography Algorithmic Toolkit (SECAT), a novel network-centric strategy for the quantitation of protein complex profiles. SECAT elucidates proteins and their context-specific PPIs in terms of both abundance and connectivity. We validate algorithm predictions using publicly available datasets and compare them to established strategies to demonstrate that SECAT represents a more scalable and effective methodology to assess protein-network state, obviating the need to infer individual protein complexes. Further, by comparing PPI-networks in interphase and mitotic HeLa cells, we demonstrate SECAT's ability to provide novel insight about context-specific molecular mechanisms that differentiate cellular states.