Background: Insulin resistance is associated with a pro-inflammatory state increasing the risk for complications in patients with type 2 diabetes mellitus (T2DM). In addition to its chronobiotic effects, the pineal hormone melatonin is also known to exert anti-inflammatory and antioxidant effects. Furthermore, melatonin was also suggested to affect insulin secretion and melatonin levels were reported to be decreased in T2DM patients Aims: The aim of this study was therefore to investigate the effect of melatonin on inflammation in diabetic rats and to study the possible involvement of the melatonin receptor, MT2. Materials and Methods: Male Sprague Dawley rats were randomly divided into four experimental groups (n = 10 per group):1) control, 2) streptozotocin/nicotinamid induced diabetes type 2 (T2DM), 3) T2DM treated with melatonin (500 µg/kg/day), and 4) T2DM treated with melatonin (500 µg/kg/day) and the selective MT2 receptor antagonist luzindole (0.25 g/kg/day). Blood samples were taken for biochemical parameters and various tissue samples (liver, adipose tissue, brain) were removed for immunohistochemistry (IHC), western blot (WB) and Q-PCR analyses, respectively. Results: Melatonin significantly reduced increased blood levels of liver transaminases (AST, ALT) and blood urea nitrogen (BUN) in diabetic rats. Furthermore, in liver and adipose tissue of treated rats, melatonin administration resulted in considerable lower expression of the increased inflammatory markers IL-1β, IL-6, TNF-α and NF-κB, as shown by reduction in RNA and protein levels. The MT2 receptor was only partly involved in the anti-inflammatory effects of melatonin. Conclusions: Our results suggest that melatonin has relevant anti-inflammatory effects in diabetic rats. Further studies in humans could prove the potential clinical benefit of melatonin supplementation in patients with T2DM.