Abstract: The present study aims to study the possible effect of the cyanobacterium Spirulina sp. as a protective agent in rats given diethylnitrosamine (DEN) in drinking water. The investigation is supposed to carried out through histopathological and immunohistochemical examinations for proliferation marker Ki67 in liver tissues. The hepatoprotective role of Spirulina shown by the histopathological examination of the liver where only little dilatation in the blood sinusoids, slight vacuolization in the cytoplasm and few pyknotic nuclei were observed. Immunohistochemical evaluation shown reduction of the number of malignant cells and its proliferation in treated group, but the Ki67 expression was high labeling index in DEN induced heptocarcinoma group. Also, liver Ki67 labeling index (Ki67 LI) in tumor tissues or adjacent non-tumor tissues were higher than that in normal liver tissues, while in tumor tissues it was higher than that in adjacent non-tumor tissues. So, using Spirulina seems to have realistic results and rapid curative effect. The development of specific therapeutic strategies based on natural algal products should be considered as an attractive approach. Based on these fascinating possibilities, Spirulina offers a great promise for patients with liver injury and Ki67 expression could represent a valuable tool in the understanding of hepatocellular carcinoma.