Among other functions, melatonin exerts both antioxidative and immunoregulatory roles. The indoleamine is secreted in the saliva, although its role into the mouth is not known. Diabetic patients frequently display oral cavity pathologies such as periodontal disease (PD), an inflammatory disease coursing with an increase in free radical production. Thus, we compared the degree of PD and interleukin-2 (IL-2) levels with melatonin concentrations in plasma and saliva of diabetic patients. A total of 43 diabetic patients (20 with type I and 23 with type II diabetes) and 20 age- and sex-matched controls were studied. Dental and medical history of all patients was in accordance with the criteria of the WHO. The periodontal status was evaluated by the Community Periodontal Index (CPI). Plasma and salivary melatonin levels were determined by specific commercial radioimmunoassays, and plasma IL-2 was measured using a commercial enzyme-linked immunosorbent assay kit. Diabetic patients had plasma and saliva melatonin levels of 8.98 +/- 7.14 and 2.70 +/- 2.04 pg/mL, respectively. These values were significantly lower (P < 0.001) than those obtained in plasma and saliva of controls (14.91 +/- 4.75 and 4.35 +/- 0.98 pg/mL, respectively). Plasma and salivary melatonin concentrations show a biphasic response in diabetic patients. Melatonin decreased in patients with a CPI index of 2, and then increased reaching highest levels in patients with a CPI index of 4. By contrast, IL-2 levels decreased from CPI index 1 to 4. The results indicate that, in diabetic patients, the presence of a marked impairment of the oral status, as assessed by the CPI index, is accompanied by an increase in plasma and salivary melatonin. The increase in salivary melatonin excretion may have a periodontal protective role.