Intravenous but not intracolonic epidermal growth factor maintains colonocyte proliferation in defunctioned rat colorectum. The role of epidermal growth factor in the proliferation of normal and premalignant colonocytes in vivo is not fully understood. In particular, the relative importance of its possible systemic and intraluminal routes of action has not been fully clarified. Rats with surgically defunctioned distal colorectums were used, and mini osmotic pumps were implanted to study the effects of intraluminal and IV administration of epidermal growth factor on colonocyte proliferation. Within 2 weeks of bypass, colonocyte proliferation in defunctioned colorectum has decreased to about one third the rate in normal colorectum or in colorectum proximal to the defunctioning colostomy. Intraluminal epidermal growth factor, infused from the time of operation did not reverse this hypoplasia, whereas IV epidermal growth factor maintained colonocyte proliferation at approximately the normal rate in bypassed colorectum. This model is suitable for testing other putative colonic mitogens for possible intraluminal and systemic effects. 