Thiazolidinediones represent an established class of insulin sensitizing agents for treating noninsulin-dependent diabetes mellitus. Darglitazone, a thiazolidinedione approximately 200ϫ more potent than ciglitazone, was evaluated in preclinical safety assessment studies using rats (1, 5, and 50 mg/kg/day) and cynomolgus monkeys (50, 75, and 100 mg/kg/day). Darglitazone was a potent adipogenic agent in rats, causing hyperplastic/hypertrophic changes and firmness of white and perirenal, dorsal thoracic (TBAT), and interscapular brown adipose tissue (BAT). Progressive changes in BAT size, morphology, firmness, and fatty acid composition preceded clinical signs of impaired respiration and the subsequent development of a dose-dependent, life-threatening hydrothorax. The characteristics of the pleural effusate were consistent with lymphatic fluid. These adverse effects were ameliorated/reversed upon drug withdrawal and were insulin-dependent since rats rendered totally insulinopenic by streptozotocin pretreatment did not develop TBAT changes or hydrothorax. Although the effects of darglitazone on BAT changes were consistent with enhanced sensitivity to endogenous glucocorticoids, adrenalectomy, and dietary dehydroepiandrosterone administration were without a protective effect. Treated monkeys also developed white and BAT hyperplasia/hypertrophy, peripheral edema, and hydrothorax-related morbidity/mortality. Both species developed reversible, dose-related reductions in red blood cell parameters and follicular atresia. Peripheral and pulmonary edema are purportedly a multifactorial process involving vasodilatation, increased endothelial permeability, and/or plasma volume expansion due to reduced renal sodium excretion. Moreover, profound alterations in TBAT hypertrophy/hyperplasia/firmness may lead to discrete hydrothorax by restricting normal thoracic lymphatic drainage. Similar effects on adipose tissue, hemodilution, and edema (peripheral and pulmonary) were observed clinically with darglitazone and/or several other structurally similar/dissimilar PPAR-␥ agonists.