In humans caffeine stimulates thermogenesis by unknown mechanisms and its effect on body weight has not been studies. The effect of placebo and 100, 200, and 400 mg oral caffeine on energy expenditure, plasma concentrations of substrates and hormones, blood pressure, and heart rate was investigated in a double-blind study in healthy subjects who had a moderate habitual caffeine consumption. Caffeine increased energy expenditure dose dependently and the thermogenic response was positively correlated with the response in plasma caffeine (r = 0.52; p less than 0.018), plasma lactate (r = 0.79; p less than 0.000001), and plasma triglyceride (r = 0.53; p less than 0.02). Stepwise regression analysis with the thermogenic response as the dependent variable excluded plasma caffeine and yielded the following equation: thermic effect (kcal/3 h) = -0.00459 X heart rate + 0.30315 X (triglyceride) + 0.53114 X (lactate) + 15.34 (r = 0.86; p = 0.0001). The results suggest that lactate and triglyceride production and increased vascular smooth muscle tone may be responsible for the major part of the thermogenic effect of caffeine.