Abstract: Melatonin plays a protective role in experimental acute pancreatitis (AP) because of its antioxidative, antiinflammatory, and immunomodulatory effects. This study presents the first data on the dynamic changes of endogenous melatonin in the early phase of human AP. Morning (08:00 hr) serum melatonin concentrations were measured by ELISA in 75 patients with AP for the first 5 days after the onset of pain. According to the Atlanta classification, 26 patients suffered a mild AP (MAP). The other 49 developed a severe AP (SAP). Median melatonin concentrations of healthy volunteers were used as a control. Median melatonin level in healthy controls was 18.5 pg/mL. Levels of melatonin were significantly higher in the first 24 hr after onset of disease in patients with MAP compared to those with SAP, 51.2 versus 8.7 pg/mL (P = 0.01). Melatonin values were the same in MAP and SAP during the remainder of the study period. Melatonin concentrations during the first 24 hr after the onset of pain in younger patients (<35 yrs old) were significantly higher than levels in older patients (>35 yrs): 73 versus 8.7 pg/mL (P = 0.01). No correlation existed between melatonin levels and the following parameters: gender, etiology (biliary versus alcohol induced), and histological findings (edematous versus necrotizing versus infected necrosis). High endogenous melatonin serum levels in the first 24 hr after the onset of AP played a protective role and favoured a mild course of the disease in humans, especially in young patients.