PPAR agonists are synthetic ligands for the peroxisome proliferator-activated receptor gamma (PPAR). These agents have insulin-sensitizing properties but can cause fluid retention, thereby limiting their usefulness in patients at risk for cardiovascular disease. The side effect etiology is unknown, but the nature of presentation suggests modulation of renal salt and water homeostasis. In a well-characterized cell culture model of the principal cell type (MDCK-C7), PPAR agonists inhibit vasopressin-stimulated Cl^- secretion with agonist dose response relationships that mirror receptor trans-activation profiles. Analyses of the components of the vasopressin-stimulated intracellular signaling pathway indicated no PPAR agonist-induced changes in basolateral membrane conductances, intracellular cAMP, protein kinase A, or total cellular adenine nucleotides. The PPAR agonist-induced decrease in anion secretion is the result of decreased mRNA of the final effector in the pathway, the apically located cystic fibrosis transmembrane regulator (CFTR). These data showing that CFTR is a target for PPAR agonists may provide new insights into the physiology of PPAR agonist-induced fluid retention.