Reactive oxygen species play an important role in the pathogenesis of respiratory distress syndrome and its complications. This study was conducted to determine if treatment with the antioxidant melatonin would influence interleukin-6, interleukin-8, tumor necrosis factor α, and nitrite/nitrate levels in newborns with grade III or IV respiratory distress syndrome (radiographically confirmed) diagnosed within the first 6 hours of life. Prior to treatment, a blood sample was collected from the umbilical cord or a peripheral vein of each newborn. Second, third, and fourth blood samples were collected at 24 hours, 72 hours, and 7 days, respectively, after beginning treatment with melatonin or placebo. Compared with the melatonin-treated respiratory distress syndrome newborns, in the untreated infants the concentrations of interleukin-6, interleukin-8, and tumor necrosis factor α were significantly higher at 24 hours, 72 hours, and at 7 days after onset of the study. in addition, nitrite/nitrate levels at all time points were higher in the untreated respiratory distress syndrome newborns than in the melatonin-treated babies. Following melatonin administration, nitrite/nitrate levels decreased significantly, whereas they remained high and increased further in the respiratory distress syndrome infants not given melatonin.