Abstract Context Cold exposure (CE) has been shown to enhance energy expenditure by activating brown adipose tissue thermogenesis and metabolism in humans. However, it remains to be elucidated if there are gender-specific differences in cold-induced thermogenesis and metabolism. Objective To study the impact of mild CE on resting energy expenditure (REE) and metabolism in males compared with females. Setting A cross-sectional study. Participants 117 healthy young Caucasians participated in this study (58 males). Mean age was 25.1 ± 3.6 years and mean body mass index 22.3 ± 1.7 kg/m2. Intervention Participants underwent a short-term CE using water perfused mattresses to activate nonshivering thermogenesis. Main Outcome Measures REE was assessed before and 2 hours after CE followed by blood sampling. Selected metabolites and hormones were measured. Skin temperatures were monitored at various sites throughout the experiment. Results Participants showed a significant increase in REE after CE (6.5%, P < .001). This increase did not differ between genders (P = .908). However, there were differences between males and females in changes of plasma glucose (–5.1% versus –7.4%, P = .024), leptin (–14.3% versus –30.1%, P < .001) and adiponectin (5.4% versus 12.8%, P = .018) after CE. We observed a significant decrease of the supraclavicular skin temperature in men (–0.3%, P = .034), but not in women (0.3%, P = .326)(P = .019 between genders). Conclusions We did not observe a difference in the thermogenic response, measured as change of REE, to CE in women compared with men. However, we found that some metabolic and hormonal changes were more pronounced in women than in men suggesting a gender-specific response to cold.