Previous studies have shown that acute increases in plasma NEFAs (non-esterified fatty acids) raise SVR (systemic vascular resistance) and BP (blood pressure). However, these studies have failed to distinguish between CNS (central nervous system) mechanisms that raise sympathetic activity and paracrine mechanisms that increase SVR directly, independent of CNS involvement. The aim of the present study was to directly determine whether the sympathetic nervous system contributes to the pressor response to NEFAs. On 2 days separated by at least 2 weeks, 17 lean healthy volunteers (ten male/seven female; age, 22+/-1 years; body mass index, 23+/-1 kg/m2; values are means+/-S.E.M.) received a 4-h intravenous infusion of 20% Intralipid or placebo (in a single-blind randomized balanced order). MSNA (muscle sympathetic nerve activity), HR (heart rate), BP (oscillometric brachial measurement) and Q (cardiac output; acetylene rebreathing) were measured before and throughout infusion. The change in HR (+8.2+/-1.0 and +2.4+/-1.2 beats/min), systolic BP (+14.0+/-1.6 and +3.2+/-2.5 mmHg) and diastolic BP (+8.2+/-1.0 and -0.1+/-1.7 mmHg) were significantly greater after the 4-h infusion of Intralipid compared with placebo (P<0.001). The change in BP with Intralipid resulted from an increase in SVR (Q/mean arterial pressure; P<0.001) compared with baseline, without a change in Q. MSNA burst frequency increased during Intralipid infusion compared with baseline (+4.9+/-1.3 bursts/min; P<0.05), and total MSNA (frequencyxamplitude) was augmented 65% (P<0.001), with no change during placebo infusion. Lipid infusion increased insulin, aldosterone and F2-isoprostane, but not leptin, concentrations. On the basis of the concomitant increase in BP, MSNA and SVR, we conclude that central sympathetic activation contributes to the pressor response to NEFAs.