The type I interferon (IFN) response protects cells against viral pathogens by inducing the transcription of hundreds of IFN-stimulated genes (ISGs). Transcriptomic and biochemical approaches have established comprehensive catalogues of ISGs across species and cell types, but their antiviral mechanisms remain incompletely characterized. Here, we apply a combination of quantitative proteomic approaches to map IFN-induced rearrangements in the human protein-protein interaction network. Specifically, we analyzed the IFN-induced changes to the HeLa cell proteome with shotgun mass spectrometry. As well, we assessed the IFN-induced interactome with protein correlation profiling coupled to size exclusion chromatography and SILAC. Finally, we utilized label-free quantitative mass spectrometry for affinity purification mass spectrometry of candidate proteins and to analyze the ribosomal protein composition.