Objective The study was undertaken to show the magnitude of interindividual differences in energy expenditure (i.e., heat production) under normal living conditions with the aim of providing physiological evidence to support the advancement of a personalized thermal conditioning approach. Methods Three sets of experimental protocols with six participants were conducted at neutral and mild cold temperatures. Energy expenditure, local skin temperatures, and core body temperature were measured continuously, while cognitive performance and thermal sensation were surveyed intermittently. The protocols were designed to study the effects of several normal day activities, low-level physical activity and eating a meal, on metabolic and physiological parameters. Results Large interindividual differences among the subjects were demonstrated using non-normalized data by design. The resting metabolic rate difference was 58%, the percentage change in energy expenditure during standing compared to sitting was up to 31%, and the difference in mechanical work efficiency between the least and the most efficient individual was 39.1%. Energy expenditure increase due to the meal effect was 11.2% to 23.3% at neutral and 9.9% to 33.9% at mild cold temperatures across individuals. Conclusions Large interindividual differences in metabolic rate under typical everyday living and office activities suggest facilitating personalized thermal conditioning instead of providing uniform temperature. Therefore, it is necessary to find noninvasive markers that can be easily measured and used as surrogates for human heat production to individualize the climate control of buildings.