The purpose of this experiment was to assess the effects of short-term overfeeding (mixed diet) on the thermic effect of a meal (TEM) and associated hormonal changes and to investigate the role of the genotype in the observed changes. Six pairs of male sedentary monozygotic (MZ) twins consumed an extra 1,000 kcal per day over their individual level of energy expenditure while maintaining a sedentary existence. Resting metabolic rate (RMR) and TEM following a 4.2 MJ meal challenge was measured before and after 22 days of overfeeding. RMR did not change significantly (7% elevation) in response to the positive caloric stimulus, whereas significant increases (P less than 0.01) in TEM were observed. Moreover, postprandial insulin and glucose responses were not modified. Overfeeding did not significantly alter catecholamine levels but induced significant elevations in plasma levels of T3 and T4 (P less than 0.05). Changes in RMR exhibited moderate but nonsignificant within twin pair resemblance in response whereas significant within pair resemblance was noted in the magnitude of TEM changes induced by overfeeding (P less than 0.05). Hormonal responses exhibited a weaker genotype dependency. These results suggest that short-term overfeeding can induce an elevation in TEM with accompanying increases in T3 and T4. Large individual response variation in metabolic and hormonal measures were observed. The similarity of response within twin pairs suggests that sensitivity to change in TEM induced by short-term overfeeding is genetically influenced.