A circadian rhythm is a biological process that has an endogenous rhythm, normally entrained to the 24-hour light dark cycle. Vasoactive intestinal peptide (VIP) has both circadian and non-circadian physiological effects. Using two strains of C57B mice (Mus musculus): a transgenic mutant with nonfunctioning VIP, and wildtype strain, we examined the effects of VIP on immune function and energy expenditure. We examined two important measures of energy expenditure: basal metabolic rate (BMR) and daily food intake (FI) and two important measures of immune function: white blood cell (WBC) count and bacterial killing assay in VIP -/- mice, at two different circadian conditions (entrained and free-running) as compared to wildtype controls. Entrained VIP -/- mice had a significantly higher BMR than wildtype mice. The BMR of entrained VIP -/- mice significantly decreased after experiencing the free-running condition. However, after experiencing the free-running condition, VIP -/- mice still had a significantly higher BMR than the wildtype mice. FI differed between the wildtype and entrained VIP-/- mice. However, after experiencing the free-running condition, the difference became more complex. VIP -/- mice had significantly lower total WBC counts as compared to the wildtypes, regardless of circadian condition. Lymphocyte and neutrophil counts did not differ between the entrained VIP -/- and wildtype mice. However, after free-running, VIP-/- mice had higher neutrophil counts and lower lymphocyte counts than the WT mice. VIP KO mice may be experiencing a more disruptive circadian condition when free-running than when entrained, which could be contributing to the reduction in metabolism.