Interleukin-6 (IL-6) deficient (-/-) mice develop mature onset obesity. Pharmacological studies have shown that IL-6 has direct lipolytic effects and when administered centrally increases sympathetic outflow. However, the metabolic functions of endogenous IL-6 are not fully elucidated. We aimed to investigate the effect of IL-6 deficiency with respect to cold exposure and cage-switch stress, that is, situations that normally increase sympathetic outflow. Energy metabolism, core temperature, heart rate, and activity were investigated in young preobese IL-6−/− mice by indirect calorimetry together with telemetry. Baseline measurements and the effect of cage-switch stress were investigated at thermoneutrality (30°C) and at room temperature (20°C). The effect of cold exposure was investigated at 4°C. At 30°C, the basal core temperature was 0.6 ± 0.24°C lower in IL-6−/− compared with wild-type mice, whereas the oxygen consumption did not differ significantly. The respiratory exchange ratio at 20°C was significantly higher and the calculated fat utilization rate was lower in IL-6−/− mice. In response to cage-switch stress, the increase in oxygen consumption at both 30 and 20°C was lower in IL-6−/− than in wild-type mice. The increase in heart rate was lower in IL-6−/− mice at 30°C. At 4°C, both the oxygen consumption and core temperature were lower in IL-6−/− compared with wild-type mice, suggesting a lower cold-induced thermogenesis in IL-6−/− mice. The present results indicate that endogenous IL-6 is of importance for stress- and cold-induced energy expenditure in mice.