We examined the effect of circadian disruption during immune challenges on energy expenditure rate in C57B mice (Mus musculus). A circadian rhythm is a biological process that has an endogenous rhythm, normally entrained to the 24-hour light dark cycle. Internal desynchronization or circadian disruption is likely to have an effect on energy expenditure such as metabolic processes. Two different experiments were performed to test the effect of disruption of circadian rhythm on energy consumption rate during an immune challenge. The first experiment involved phase shifting a normal C57B mouse strain in order to simulate a jet lag effect (compared to controls) and then all mice were injected with a noninfectious mild antigen (immune challenge). The second experiment involved working with a transgenic mouse strain, which becomes circadian disrupted when kept in constant darkness (compared to controls) and all mice experienced an innate (LPS) immune challenge. We examined two important measures of energy expenditure: basal metabolic rate (BMR) and daily food intake (FI). Before antigen challenge, we found no difference in BMR between control and phase shifted mice. However, after the antigen challenge a difference developed in BMR between phase shifted and controls. FI does change with time both before and after antigen challenge, however the effect is complex. BMR did not significantly differ between light cycles before and after LPS for either mouse strain. Our results are important for understanding effects of circadian misalignment in humans who regularly experience circadian disruption, such as shift workers and those experiencing jet lag.