Aim: Melatonin is a potent free radical scavenger and an indirect antioxidant. Knowledge about the behavior of melatonin secretion in the early neonatal period, which may relate to its properties at a vital stage during very high antioxidant demands, is limited. Patients and Methods: We studied 35 newborns admitted to the Neonatal Unit with respiratory distress syndrome (RDS) and with no signs of sepsis, severe anemia, hemodynamic compromise or malformation. The gestational age of the newborns was 26–40 weeks (mean value 32.5 weeks) and the weight at birth was 870–4,400 g (mean value 1,800 g). They were classified into two groups: ≤1,500 g or >1,500 g birthweight. In all cases, at 09:00 h on their 1st, 3rd and 7th days of life, serum melatonin was measured by RIA. The clinical history was recorded and treatment and follow-up were performed according to established neonatology practice, and the resultant data recorded. Informed consent from the parents or guardians was obtained in accordance with the Declaration of Helsinki. Statistical analysis was carried out using ANOVA-II (factor I: day of sample; factor II: birthweight). Results: There were significant increases in melatonin levels with increasing birthweight (p = 0.017), but no changes by day of sample. Although in both study groups melatonin levels increased during the first few days this was not statistically significant. Conclusions: In newborns of low birthweight, we report high melatonin concentrations in the morning and during the first week of life. These increase with maturation, and at full-term were similar to nocturnal levels during the acrophase of pineal gland secretion in toddlers and schoolage children, when pineal gland secretion is maximal and takes place reflecting environmental variations. In the early neonatal period these high levels of melatonin seem to derive from extrapineal sources, which mature to provide antioxidant protection in accordance with other elements of the antioxidant network to compensate for the high levels of oxidative stress that are present in the perinatal period.