During the fasting state, insulin reduces NEFA appearance in the systemic circulation mostly by suppressing intracellular lipolysis in the adipose tissue. In the postprandial state, insulin may also control NEFA appearance through enhanced trapping into the adipose tissue of NEFA derived from intravascular triglyceride lipolysis. To determine the contribution of suppression of intracellular lipolysis in the modulation of plasma NEFA metabolism by insulin during enhanced intravascular triglyceride lipolysis, ten healthy non-obese subjects underwent pancreatic clamps at fasting vs. high physiological insulin level with IV infusion of heparin + Intralipid. Nicotinic acid was administered orally during the last 2 hours of each 4-hour clamp to inhibit intracellular lipolysis and to assess insulin's effect on plasma NEFA metabolism independent of its effect on intracellular lipolysis. Stable isotope tracers of palmitate, acetate, and glycerol were used to assess plasma NEFA metabolism and total triglyceride lipolysis in each participant. The glycerol appearance rate was similar during fasting vs. high insulin level but plasma NEFA levels were significantly lowered by insulin. Nicotinic acid significantly blunted the insulin-mediated suppression of plasma palmitate appearance and oxidation rates by approximately 60% and 70% respectively. In contrast, nicotinic acid did not affect the marked stimulation of palmitate clearance by insulin. Thus, most of the insulin-mediated reduction of plasma NEFA appearance and oxidation can be explained by suppression of intracellular lipolysis during enhanced intravascular triglyceride lipolysis in healthy humans. Our results also suggest that insulin may affect plasma NEFA clearance independently of the suppression of intracellular lipolysis.