Portal hypertension impedes outflow from the splanchnic vascular beds. We hypothesized that the increase in splenic intravascular pressure may initiate a neural reflex to increase mesenteric arterial tone and reduce blood flow into the plethoric mesenteric vascular bed. Splenic venous pressure was selectively increased by partial splenic vein occlusion (6.9±0.5 to 22.5±0.3 mmHg, n=47). During the 3 minutes following occlusion, mesenteric vascular conductance fell (−0.01±0.002 mmHg/mL·min‐1; p<0.05 n=7), an effect which was unchanged by renal denervation (−0.01±0.009 mmHg/mL·min‐1; n=6) and exacerbated by mesenteric denervation (−0.02±0.004 mmHg/mL·min‐1; p<0.05, n=7). The fall in conductance was abolished by splenic denervation (−0.002±0.002 mmHg/mL·min‐1; p<0.05 n=6). Similarly, the significant increase in mesenteric efferent nerve activity observed during splenic venous occlusion (22.2±2.8 to 27.9±3.8 spikes/sec, p<0.05 n=13) was absent after splenic denervation (32.4±2.4 to 31.2±1.6 spikes/sec, n=7). Although the spleen is thus integral to initiating the reflex, the accompanying increase in mesenteric nerve activity is not wholly responsible for increasing mesenteric arterial tone. (HSFC,CIHR).