Morphine, an opiate alkaloid with mixed mu- and delta-agonist properties, raises the ventricular fibrillation threshold in anesthetized dogs by altering autonomic tone. To elucidate further underlying structure-activity relationships, the effect of fentanyl, a nonalkaloid, mu-selective agonist in wide clinical use, was studied. Fentanyl (30 micrograms/kg) was given intravenously to 27 chloralose-anesthetized dogs, and ventricular fibrillation threshold was measured by means of the single-stimulus technique. In the baseline state fentanyl raised the ventricular fibrillation threshold by 14%. When the dogs were subjected to hemorrhagic stress, this effect was amplified to 29% (p less than 0.0001). Bilateral cervical vagotomy abolished fentanyl's antifibrillatory effect, but neither atropine sulfate (0.4 mg/kg/hr) nor atropine methylnitrate (0.5 mg/kg/hr) did so. Fentanyl's influence on the fibrillation threshold during hemorrhage was significantly reduced by bilateral stellate ganglionectomy (p less than 0.005). It is concluded that fentanyl raises the ventricular fibrillation threshold by its known sympathoinhibitory action rather than by its vagal efferent activating effect. The facts that an intact vagus is required and that hemorrhage amplifies the effect suggest that the antifibrillatory effect of fentanyl is mediated through the afferent component of the baroreflex arc.