Fibroblast growth factor‐2 (FGF‐2) is a heparin‐binding protein capable of inducing angiogenesis in multiple animal models of chronic ischemia. The pharmacokinetics and pharmacodynamics of a single dose of recombinant FGF‐2 (rFGF‐2) administered by intracoronary or intravenous infusion were evaluated in a Phase I trial in 66 patients with severe coronary artery disease. rFGF‐2 displayed biphasic elimination with a mean studywide distribution t_1/2 of 21 minutes and a mean apparent terminal elimination t_1/2 of 7.6 hours. Systemic exposure to rFGF‐2 was comparable following intracoronary or intravenous administration. Peak plasma concentration and area under the concentration‐time curve increased proportionally with dose, indicating linear pharmacokinetics over the dose range examined (0.33 to 48.0 μg/kg). Greater systemic exposure was observed when heparin was administered closer to rFGF‐2 infusion, consistent with slower clearance of heparin/rFGF‐2 complexes. Infusion of rFGF‐2 was associated with changes in acute hemodynamics. While a clear PK/PD dose‐response relationship was not established, a trend toward hypotension and tachycardia with higher rFGF‐2 doses was observed.