We studied the effects of thiazolidinedione treatment (rosiglitazone 1 or 10 μmol · kg⁻¹ · day⁻¹ or darglitazone 1.3 μmol · kg⁻¹ · day⁻¹ for 3 weeks) on lipid metabolism in obese Zucker rats. In the basal 7-h fasted state, rosiglitazone (10 μmol · kg⁻¹ · day⁻¹) and darglitazone corrected the hypertriglyceridemia by increasing plasma triglyceride (TG) clearance and decreasing hepatic TG production, as assessed using Triton WR 1339. Free fatty acid (FFA) metabolism was assessed using ³H-palmitate tracer by estimating rates of plasma FFA appearance (R_a), whole-body FFA oxidation (R_ox), and tissue-specific nonoxidative FFA disposal (R_fs). Basal R_a, plasma FFA levels, and clearance were increased by both thiazolidinediones. Detailed studies were conducted with darglitazone, which under basal conditions increased R_a (+114%), R_ox (+51%), and R_fs in adipose tissues. During euglycemic clamps performed at insulin levels corresponding to those observed postprandially, darglitazone increased the glucose infusion rate from 4.7 to 13.3 mg · min⁻¹ and, in contrast to the basal state, it decreased R_a (−67%), R_ox (−84%), and R_fs in adipose tissue, muscle, and liver. We concluded that thiazolidinediones 1) ameliorate hypertriglyceridemia by lowered hepatic TG production and augmented TG clearance (two separate kinetic effects), 2) enhance insulin-mediated suppression of systemic FFA mobilization while increasing the capacity to mobilize FFA during fasting, 3) increase FFA trafficking into adipose tissue by increasing the ability of adipose tissue to take up and store FFA, and 4) enhance metabolic flexibility by improving glucoregulation under hyperinsulinemic conditions (possibly involving reduced skeletal muscle and liver exposure to fatty acids) and augmenting the capacity to utilize FFAs during fasting.