The aim of the present study was to investigate the long-term and high-dose application of ketamine on the liver by employing histologic and biochemical methods. A total of 30 male rats were randomly assigned to control and four treatment groups (n: 6). Saline for control group and different doses of ketamine for four treatment groups (40, 60, 80 and 100mgkg(-1)) were administered intraperitoneal twice a day for 2weeks. Immunohistological staining, light and electron microscopy were used to study tissue specimens. Histopathological changes were more severe and diverse in groups 80 and 100mgkg(-1)day(-1), and the least significant change was observed in groups 40 and 60mgkg(-1)day(-1). The most important ultrastructural changes were seen in mitochondria and in the rough endoplasmic reticulum. The immunoreactivity of calcineurin was determined as different. Prolonged use of ketamine caused hepatocellualar toxicity and histological changes in hepatocytes in a dose-dependent manner in all experimental groups.