Eighteen hospitalized patients dependent on total parenteral nutrition (TPN) were randomly enrolled into a prospective study comparing intravenous long‐chain triglycerides (LCT) with a physical mixture of 75% medium‐chain triglycerides (MCT) and 25% LCT. The TPN was given continuously as amino acids and glucose over 5 days with the respective lipid emulsion given intermittently during each day for 10 hr. Indirect calorimetry was measured on each patient before the lipid emulsion was administered in the morning and again 10 hr later near the end of the lipid infusion, on days 1, 3, and 5. Resting energy expenditure, VO2, VCO2, and calculated fat oxidation were shown to increase during MCT infusion but not during LCT administration, (resting energy expenditure 899 ± 37 to 1085 ± 40, compared with 978 ± 23 to 976 ± 39, kcal/m2body surface area [BSA]/day, respectively, p<0.0002; V02: 129.9 ± 5.2 to 157.2 ± 5.9, compared with 140.9 ± 3.6 to 141.2 ± 5.9 ml O2/min/m2BSA, respectively, p<0.0005; and VCO2: 110.7 ± 4.4 to 127.5 ± 4.3, compared with 118.3 ± 2.8 to 118.0 ± 5.3, ml CO2/min/m2BSA, respectively, p<0.0076; calculated fat oxidation 10.7 ± 1.5 to 19.3 ± 2.4, compared with 20.0 ± 2.7 to 20.0 ± 3.6, kcal/m2BSA/hr, respectively, p<0.014). Respiratory quotient tended to fall with lipid infusion but did not change statistically. Body temperatures were unaltered by either fat infusion. It is concluded that TPN consisting of MCT causes an increased thermogenesis, most likely through increased fat oxidation, reflective of MCT's property as an obligate fuel. The increased thermogenesis occurs without an increase in body temperature.(Journal of Parenteral and Enteral Nutrition15:27–31, 1991)