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In this study, the protective effect of melatonin was investigated in lipopolysaccharide induced sepsis model. Twenty‐eight rats were randomly divided: Control, Melatonin, LPS and LPS + Melatonin. After LPS application, surgically remove kidney and liver tissues. The level of malondialdehyde (MDA) an oxidative stress marker and the immunoreactivity of Toll‐like receptor‐4 (TLR4), tumor necrosis factor‐α (TNF‐α), and transcription factor NF‐κB were evaluated immunohistochemically. Expression levels for TLR4, TNF‐α, NF‐kB, IL‐1β (interleukin 1 beta), and IL‐6 (interleukin 6) were evaluated. Additionally, Argyrophilic NOR staining was performed in tissues. Vacuolization and inflammation were more intense in the kidney and liver sections in the LPS group compared to the other groups. It was observed that vacuolization and inflammation were decreased in LPS + Melatonin applied groups. It was determined …