In recent years, protein footprinting coupled with mass spectrometry has been used to identify protein-protein interaction sites and regions of conformational change through modification of solvent accessible sites in proteins. The footprinting method, fast photochemical oxidation of proteins (FPOP), utilizes hydroxyl radicals to modify these solvent accessible sites. To date, FPOP has been used in vitro on relatively pure protein systems. We have further extended the FPOP method for in vivo analysis of proteins. This will allow for study of proteins in their native cellular environment and be especially useful for the study of membrane proteins which can be difficult to purify for in vitro studies. A major application of the in vivo method is for proteome-wide structural biology. In a first application of the method, we have applied IC-FPOP for the identification of drug-induced interactome changes. IC-FPOP was performed on K562 cells, a myelogenous leukemia cell line, in the presence of absence of the cancer drug methotrexate. In total, 1067 proteins were modified reproducibly in both conditions. Of these, several hundred demonstrated differences in global oxidation of proteins after drug treatment. Many of these proteins are localized in the folate acid cycle pathway, downstream of the methotrexate target, dihydrofolate reductase (DHFR). Peptide-level quantification of these proteins show that these changes are due to protein interaction changes downstream of DHFR. This work demonstrates the power of IC-FPOP for structural biology across the proteome.