Context: Cold-induced activation of thermogenesis modulates energy metabolism, but the role of humoral mediators is not completely understood.Objective: To investigate the role of parathyroid and thyroid hormones in acute and adaptive response to cold in humans.Design: Cross-sectional study examining acute response to ice-water swimming and to experimental non-shivering thermogenesis (NST) induction in individuals acclimatized and non-acclimatized to cold. Seasonal variation in energy metabolism of ice-water swimmers and associations between circulating PTH and molecular components of thermogenic program in brown adipose tissue (BAT) of neck-surgery patients were evaluated.Setting: Clinical Research Center.Patients, Participants: Ice-water swimmers (winter swim n=15, NST-induction n=6), non-acclimatized volunteers (NST-induction, n=11, elective neck surgery n = 36).Main Outcomes and Results: In ice-water swimmers, PTH and TSH increased in response to 15min winter swim, while activation of NST failed to regulate PTH and lowered TSH. In non-acclimatized men, NST-induction decreased PTH and TSH. Positive correlation between systemic levels of PTH and whole-body metabolic preference for lipids as well as BAT 18F-FDG uptake was found across the two populations. Moreover, NST-cooling protocol-induced changes in metabolic preference for lipids correlated positively with changes in PTH. Finally, variability in circulating PTH correlated positively with UCP1/UCP1, PPARGC1A and DIO2 in BAT from neck surgery patients.Conclusions: Regulation of PTH and thyroid hormones during cold exposure in humans depends on the cold acclimatization level and/or cold stimulus intensity. Role of PTH in NST is substantiated by its positive relationships with whole-body metabolic preference for lipids, BAT volume and UCP1 content.