This project contains label-free LC-MS/MS interactome proteomics data from anti-SDC3 and matched IgG immunoprecipitates of hypoxia-conditioned mouse bone marrow-derived macrophages cultured on fibronectin-coated soft or stiff matrices. The experimental groups are Soft + anti-SDC3 IP, Stiff + anti-SDC3 IP, and Stiff + IgG IP. The dataset was generated to define SDC3-associated proteins and identify matrix stiffness-dependent remodeling of the SDC3 interactome.