Macrophages polarize into distinct phenotypes in response to complex environmental cues. We found that the nuclear receptor PPARγ drove robust phenotypic changes in macrophages upon repeated stimulation with interleukin (IL)-4. The functions of PPARγ on macrophage polarization in this setting were independent of ligand binding. Ligand-insensitive PPARγ bound DNA and recruited the coactivator P300 and the architectural protein RAD21. This established a permissive chromatin environment that conferred transcriptional memory by facilitating the binding of the transcriptional regulator STAT6 and RNA polymerase II, leading to robust production of enhancer and mRNAs upon IL-4 re-stimulation. Ligand-insensitive PPARγ binding controlled the expression of an extracellular matrix remodeling-related gene network in macrophages. Expression of these genes increased during muscle regeneration in a mouse model of injury, and this increase coincided with the detection of IL-4 and PPARγ in the affected tissue. Thus, a predominantly ligand-insensitive PPARγ:RXR cistrome regulates progressive and/or reinforcing macrophage polarization. Display omitted •Ligand-insensitive PPARγ sites are highly abundant in alternatively polarized MQs•PPARγ is recruited to the genome in a ligand-independent manner upon polarization•Ligand-insensitive PPARγ alters chromatin structure and facilitates IL-4 signaling•Ligand-insensitive PPARγ drives progressive polarization via transcriptional memory Daniel et al. describe that the nuclear receptor PPARγ has a significant ligand-insensitive, genome-bound fraction that affects local chromatin structure upon macrophage polarization. Ligand-insensitive PPARγ mediates the expression of a hidden gene set upon repeated IL-4 exposure, providing transcriptional memory and an epigenomic ratchet mechanism to support progressive polarization.