Significance During pregnancy, high circulating levels of adenosine and prostaglandins reduce the ability of fetal immune cells to mount powerful proinflammatory responses. In contrast, newborns express 10-fold higher levels of the proinflammatory immune regulator migration inhibitory factor (MIF) compared with adults. MIF sustains cell activation and cytokine production and counterregulates adenosine and prostaglandin E2-mediated immunosuppression in newborn monocytes. Yet excessive MIF expression during an established infection worsens the outcome of newborn mice. Thus, we identify a unique role for MIF in regulating neonatal innate immune responses and propose that MIF has a protective role to reduce susceptibility to infection during the neonatal period but may favor uncontrolled inflammation during sepsis, leading to adverse outcomes.