This study reports the clinical signs and gross and histopathological changes that occurred in liver and intestine of male rats given alcoholic extract of citrullus colocynthis fruits. The LD50 was determined by the up-and-down method. The second part aimed to determine the dose that does not cause death of rats but revealed the toxic effect of alcoholic extract of citrullus colocynthis fruits and reveal the toxic signs and pathological changes at 1-6th week of treatment at 300 mg/kg, orally. Result showed that the LD50 of citrullus colocynthis fruit extract was 373.7 mg/kg of body weight, while the dose of 300 mg/kg of body weight was the best dose that lead to appearance of clinical signs of toxicity during 1-2 hours after administration. The main clinical signs were depression, inappetance, accumulation in groups and hemorrhagic diarrhea; these signs increased in the second week and decreased in severity at the end of the experiment. The gross pathological lesions were congestion of the internal organs especially liver and mucus material was found in the intestinal lumen. The histopathological changes included fatty change with congestion of sinosoids and infiltration of inflammatory cells in portal areas. Mucinous degeneration with sloughing of epithelial cells and hyperplasia were seen in the intestine.