Epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) bind to a common receptor and are both present in the normal gastrointestinal tract. Although many studies have examined their function in isolation, there is little information directly comparing their actions. We examined the relative potency of TGF alpha and EGF in stimulating 3H-thymidine uptake into primary rat hepatocytes at various doses in vitro and on the crypt cell production rate (CCPR) within the gastrointestinal tract when infused intravenously at 49 nmol/kg/day into rats receiving total parenteral nutrition. In vitro, maximal stimulatory activity was similar in EGF- and TGF alpha-treated cells, however, the dose of EGF required to stimulate 3H-thymidine uptake to 50% of maximal levels was only one third of that required using TGF alpha. In vivo, EGF and TGF alpha significantly increased the weight and proliferative indices throughout the gastrointestinal tract. The response (as determined by CCPR) was about 80% higher in animals which had received EGF when compared to animals receiving TGF alpha. Treatment with EGF also caused significant rises in plasma PYY, enteroglucagon and gastrin levels, whereas the equivalent dose of TGF alpha only caused a significant rise in plasma gastrin levels. We conclude that TGF-alpha, like EGF, is trophic to the entire gastrointestinal tract of the rat, however, it is a less effective mitogen, and has differential hormonal effects.