Background: As endotherms, humans face the vital challenge of maintaining an elevated and constant body temperature under varying environmental conditions, through the metabolic production of heat (thermogenesis). However, despite many decades of research aimed at understanding the thermoregulatory responses under varying cold stresses, very little is known regarding the variability in the thermogenic responses and the influence of skin temperature in this variability. Therefore, the aim of this study is to assess the relationship between skin cooling and the resulting heat production, shivering responses, and the resulting oxidative fuel selection in cold-exposed men and women to better understand the determinants in the cold-defence responses in humans. Methods and Results: By combining indirect calorimetry with surface electromyography, we examined substrate utilization, shivering intensity and muscle fiber recruitment when clamping skin temperature at 3 different temperatures (31°C, 29 °C and 27 °C) using a liquid-conditioned suit to provide a controlled uniform stimulus. Using this paradigm, we were able to carefully characterize the effect of skin temperature on thermogenesis and fuel selection in lean, healthy men (n=12) and women (n=12) and investigate its relationship with the subjective evaluation of thermal sensation. In addition, we examined whether sex-differences in cold-induced shivering intensity and fuel selection persist when exposing men and women to the same mean skin temperature. Our results showed a skin temperature-dependent increase in shivering intensity and metabolic heat production (P < 0.0001), including sex-dependent difference in heat production at all three skin temperatures (31°C: P =0.0003; 29°C: P = 0.0009; 27°C: P = 0.0041). Using an 11-point thermal comfort like scale, participants reported feeling progressively colder with every 2°C decrease in mean skin temperature compared to the baseline period (P < 0.0001). At a skin temperature of 27°C the shivering burst rate (27 vs. 31: P = 0.0097; 27 vs. 29: P = 0.0376), burst shivering intensity (27 vs. 31: P < 0.0001; 27 vs. 29: P = 0.0002) and continuous shivering intensity (27 vs. 31: P = 0.0001; 27 vs. 29: P = 0.0172) were all significantly higher than at a skin temperature of 29°C and 31°C. Nevertheless, our results show that although participants were all clamped at the same skin temperature there was significant variability in both metabolic heat production and shivering intensity between individuals. Conclusions: These data suggest that heat production, shivering intensity, shivering pattern, and thermal comfort change in a temperature-dependant fashion. Apart from the metabolic heat production, these responses are similar between men and women. Despite clamping mean skin temperature at 3 different temperatures, there was tremendous inter-individual variability in the means used to defend their core temperatures. While whole-body heat loss and the consequent increase in metabolic heat production appears to be driven primarily by physical properties such as differences in body mass, body composition or body surface area, the varied shivering responses may be determined by factors such as genetics, training status or regular cold exposure. Further work is required to examine the thermogenic mechanisms that are recruited under these various skin temperatures.