Objectives: The goal of this study was to explore the effects of angiogenic gene therapy. Background: Preclinical studies with intracoronary administration of Ad5FGF-4 (alferminogene tadenovec, Generx, Berlex Biosciences, Richmond, California) suggested it could induce angiogenesis and provide a new clinical approach to the treatment of chronic angina pectoris. Two preliminary clinical trials provided evidence that it could improve exercise treadmill test (ETT) time and myocardial perfusion. The AGENT (Angiogenic GENe Therapy)-3 and -4 trials of a low and high dose of Ad5FGF-4 for chronic angina were initiated in the U.S. and other countries and enrolled 532 patients in a randomized, double-blind, placebo-controlled fashion. Both studies were halted when an interim analysis of the AGENT-3 trial indicated that the primary end point change from baseline in total ETT time at 12 weeks would not reach significance. Methods: We performed a pooled data analysis from the 2 nearly identical trials to investigate possible treatment effects on primary and secondary end points in prespecified subgroups. Results: The effect of placebo was large and not different than active treatment in men, but the placebo effect in women was negligible and the treatment effect was significantly greater than placebo. We found a significant, gender-specific beneficial effect of Ad5FGF-4 on total ETT time, time to 1 mm ST-segment depression, time to angina, and Canadian Cardiovascular Society class in women. This is the first clinical report of a gender difference in response to cardiac angiogenic therapy. Conclusions: The potential importance of the observed gender-specific angiogenic response on the clinical treatment of refractory angina is substantial and deserves further investigation. (Efficacy and Safety of Intracoronary Ad5FGF-4 in Patients With Stable Angina; http://www.clinicaltrials.gov/ct/show/NCT00346437; NCT00346437) (Safety and Efficacy of Intracoronary Ad5FGF-4 in Patients With Stable Angina [AGENT-4]; http://www.clinicaltrials.gov/ct/show/NCT00185263; NCT00185263) (AWARE; http://www.clinicaltrials.gov/ct/show/NCT000438867; NCT000438867).