Colorectal cancer is the third most common cancer worldwide. However, it considered as preventable and treatable disease. This study was designed to evaluate the efficacy of metformin when given by different routes (Oral and intraperitoneal route) in preventing the formation of colon cancer biomarker (Aberrant crypt foci) that induced in mice and also to study the antiproliferative effect of metformin in comparison with 5-floururacil on the colonic epithelial cells. Sixty Swiss albino BALB/c mice of six weeks of ages weighing between 18-22gm were used in this study. They were equally divided into five groups (12 mice each). Mice of each group (except negative control group) were injected intraperitoneally with azoxymethane (10mg/kg) once weekly for two weeks then one week the second dose of azoxymethane they were treated for four weeks with one of the following drugs: Group A treated with normal saline (Positive control group); group B treated with metfromin orally dissolved in the drinking water in concentration of 5mg/ml; group C treated with metformin intraperitoneally (250mg/kg/ day) in 2 divided doses; group D treated with 5-floururacil intraperitoneally (15 mg/kg/day) six times weekly& group E negative control (did not receive drug). After six weeks all mice were scarified and examined for the formation of colonic aberrant crypt foci. Proliferating cell nuclear antigen (PCNA) labeling index was used to investigate the antiproliferative effect of metformin comparing to 5-floururacil.This study also include measurement the level of fasting blood sugar, total serum cholesterol and serum triglyceride to exclude any indirect effect of metformin. Besides, body weight was measured weekly to show any change in their weight during the course of the treatment. The results demonstrated that both 5- floururacil and metfromin (orally and intraperitoneally) showed highly significant reduction in the numbers of aberrant crypt foci in colon of mice comparing to positive control group (P <0.001). Highly significant difference in the number of aberrant crypt foci was observed between 5-FU treated mice and oral metformin mice (P<0.001). While no significant difference occurred between 5-FU treated group and those treated with metformin intraperitoneally (P> 0.05). Immunohistochemical analysis of PCNA labeling index observed that orally metformin treated group, intraperitoneally metformin treated group and 5-FU treated group, were significantly lower than positive control group (p<0.05). While no significant differences observed between group E ( negative control group) and group C or D (P > 0.05).However, significant differences observed between group E and group A or B (P < 0.05). Analysis of data revealed that metformin (given orally or intraperitoneally) did not show any significant effect on the level of fasting blood sugar, total serum cholesterol, serum triglyceride comparing to untreated mice (Group A & E) (P> 0.05).While 5-FU treated mice showed significant effect in all above serum analysis when compare with other group in the experiment (P< 0.05). During the course of the treatment, metformin did not show a clear effect on the body weight of the mice whether given orally or by intraperitoneally route (P> 0.05).Whereas, the body weight of mice in the group treated with 5-FU drug was markedly reduced (P< 0.05) compared to other groups in the experiment. In conclusion, metformin may be play an important role in preventing the colorectal carcinogenesis by suppression the formation of aberrant crypts foci without causing any change in the level of fasting blood glucose, total serum cholesterol, serum triglyceride, and body weight during the course of the treatment. Both metformin and 5-FU have significant antiprliferative activity against proliferation of colonic epithelium. Intraperitoneal administration of metformin has more chemopreventive effect and more antiproliferative effect than oral administration so as its efficacy become close to that of 5-FU without significant difference between them.