Macrophage migration inhibitory factor (MIF) plays a pivotal role in pregnancy-related proinflammatory processes, such as placentation and labor. Differential MIF concentrations have been correlated with pathological events during pregnancy, such as recurrent miscarriages and severe pre-eclampsia (PE). The aim of this study was to prospectively investigate whether maternal MIF serum levels are already altered in early pregnancy before PE onset. Women (n=2,821) before 20 weeks of gestational age were recruited for a prospective study on early markers of PE. Forty-eight consecutive pregnancies that developed PE and 79 normotensive pregnancies that delivered at term were chosen. Maternal MIF serum levels were assessed by ELISA. We found significantly lower MIF serum levels in women who developed PE (4,967 ± 3,119 pg/mL) compared to controls (7,640 ± 5,519 pg/mL) (mean ± standard deviation, P<0.001). Our findings indicate that low maternal MIF serum levels in early pregnancy may contribute to abnormal placental development.