Objective: Brown adipose tissue (BAT) activity in humans is stimulated by cold and by a limited number of pharmacological agents, including β3-adrenergic agonists and bile acids. Although thyrotropin-releasing hormone (TRH) is known to activate BAT in several mammals, this has not been reported in humans. Design: A randomized, placebo-controlled, double-blind, cross-over trial. Methods: We investigated the effects of intravenous bolus administration of 400µg TRH or 2mL saline on BAT activity in healthy, lean men. BAT activity was measured as standardized18F-fluorodeoxyglucose (18F-FDG) uptake and glucose metabolic rate (MRglu) using dynamic PET/CT imaging. The first six individuals were studied at room temperature, while subsequently nine were exposed to mild cold (17°C±1°C) for 60min before imaging. During the dynamic scan, blood was withdrawn for measurement of thyroid hormone and catecholamine concentrations. This trial is registered with The Netherlands National Trial Register (number NTR5512). Results: Sixteen participants were recruited. Six men studied at room temperature showed no visible BAT activity during either session. After exposure to mild cold, four of nine men (44.4%) showed clear increase of18F-FDG uptake after TRH administration compared to placebo. Maximal standardized18F-FDG uptake showed a trend toward increase after TRH compared to placebo (P=0.066). MRglu showed a significant increase after TRH administration (P=0.014). The increase in18F-FDG uptake was not paralleled by changes in plasma thyroid hormone or catecholamine concentrations. Conclusion: Systemic TRH administration can increase the activity of cold-stimulated BAT in adult men. These findings may assist developing pharmacological strategies for modulating BAT activity in the management of obesity.