Corticotropin-releasing factor (CRF), a peptide neurotransmitter, is suggested as a novel agent to reduce reperfusion edema following ischemia. In a rat hind limb replantation model, animals underwent amputation followed by 2.5 hours of ischemia with replantation and 2 hours of reperfusion. Animals were randomized to seven groups: a nonischemic control group and six experimental groups receiving treatment prior to reperfusion with (1) saline control, (2) alpha 9,41-CRF—a CRF receptor blocking agent (98 µg/per kilogram), (3) subcutaneous CRF (320 µg/per kilogram), (4) intravenous CRF (80 µg/per kilogram), (5) alpha- CRF and subcutaneous CRF, and (6) alpha-CRF and intravenous CRF. Comparison of preischemic amputated limb weight with weight after ischemia and reperfusion showed a reproducible and significant gain in limb weight after 2 hours (p=0.004). A significant reduction in limb weight gain (49%) was achieved with both subcutaneous (p<0.04) and intravenous CRF (p<0.036). With the dose used in this model, alpha 9,41 CRF attenuated but did not completely block the effects of intravenous or subcutaneous CRF.