Aims: The risk of neonates for severe infection/sepsis is reciprocally proportional to gestational age and birth weight. As monocytes and dendritic cells (DC) are recognised key antigen-presenting immune cells, we aimed to elucidate whether neonatal age is associated with reduced expression of human-leukocyte antigen-DR (HLA-DR) antigens on subsets of monocytes and DCs. Methods: Forty-three consecutive neonates (20 male, mean gestational age 236.0 ± 26.8 days; mean 1-min Apgar score 7.5 ± 2.0) were included in a monocentric prospective observational analysis. Patients were grouped according to gestational age (n = 15 full-term, n = 28 pre-term defined as < 33 weeks). Ten healthy adult volunteers were assessed also. Flow-cytometric assessment of HLA-DR expression was performed in subsets of peripheral blood myeloid and plasmacytoid DCs (MDC and PDC) and monocytes (CD14 bright-CD16 negative /CD14 positive CD16 positive /CD14 dim CD16 positive ). Clinical and routine laboratory data were followed up. Results: At birth, leukocyte counts were increased in full-term neonates. Monocyte counts were significantly increased in neonates when compared with adults (all P < 0.05). A significant numerical increase of CD14 bright-CD16 negative and CD14 positive CD16 positive monocytes was noted in pre-term and full-term neonates (all P < 0.05), while HLA-DR expression in these subsets was significantly diminished (most pronounced in pre-term infants, P < 0.0001). MDC and PDC HLA-DR expression was reduced also (all P < 0.05). Clinical indices (e.g., pH, days on antibiotics/mechanical ventilation, fever/sepsis) were not found to correlate with immunological indices. Conclusions: We observed a markedly diminished HLA-DR expression on monocyte and DC subsets in pre-term and full-term neonates, which may contribute to impaired antimicrobial defence mechanisms in the early days of life.