To determine the influence of background vasomotor tone on the effectiveness of sodium nitroprusside in decreasing total peripheral resistance, experiments were performed on 12 open-chest dogs under halothane anesthesia. In the first experiment, the vasomotor condition of six dogs was changed by altering the background infusion rate of phenylephrine (0, 40, and 0 μg/min). Increasing background phenylephrine infusion from 0 to 40 μg/min significantly enhanced the effectiveness of nitroprusside in decreasing total peripheral resistance. In contrast, the effectiveness of nitroprusside in decreasing arterial pressure was not altered significantly. In a second experiment on six other dogs, phenylephrine was infused continuously at 40 μg/min, and the vasomotor condition was changed by the infusion of phentolamine (0, 60–100, 0 μg/min). Phentolamine significantly diminished the effectiveness of nitroprusside in decreasing peripheral resistance. In contrast, the effectiveness of nitroprusside in decreasing arterial pressure was not altered significantly. Stepwise linear regression analysis indicated that the background peripheral resistance was the hemodynamic variable that could account partially for the changes in nitroprusside effectiveness. Increasing background total peripheral resistance significantly enhanced the effectiveness of nitroprusside in decreasing total peripheral resistance.