The notion that paraxanthine (the major dimethylated by-product of caffeine) may be a biologically active metabolite that could mediate some of the effects of caffeine was tested in relation to the well-established property of caffeine as a thermogenic stimulant. From studies measuring the in vitro respiration rates of rat brown adipose tissue in the basal state and in response to ephedrine (an enhancer of norepinephrine release from sympathetic nerve endings), it is shown that paraxanthine has the same potency as its parent compound, caffeine, in interacting with the adrenergic system to potentiate thermogenesis. These data provide the first direct demonstration of a physiological effect of the main metabolite of caffeine and raise the possibility that paraxanthine may contribute importantly to the ability of caffeine to potentiate the thermogenic effects of well-known stimuli of the sympathetic nervous system such as cold exposure, moderate exercise, and sympathomimetic drugs.