Preterm neonates are susceptible to infection due to a combination of sub-optimal immunity and increased exposure to invasive organisms. Mannose-binding lectin (MBL) is a component of the innate immune system, which may be especially important in the neonatal setting. The objective of this study was to investigate the impact of MBL on susceptibility and severity of infection in preterm neonates during their first month of life. One hundred fifty eight preterm neonates were genotyped for MBL mutations by heteroduplex analyses. Consecutive serum MBL levels were measured by ELISA and clinical and laboratory data, including blood cultures, were collected for each baby. A third of the premature neonates had genetically determined MBL deficiency. In addition, MBL levels were also low in the first week of life and lower in neonates with a wild type genotype who were less than 28 wk gestation or a birth weight of less than 1000 g, thereby increasing the number of neonates with a low MBL level at birth. MBL deficiency was associated with an increased risk of sepsis (p < 0.01). This study indicates that MBL levels are low in neonates at birth and renders premature neonates to an increased risk of infection.