Evidence is presented that the liver effects an essentially complete degradation of plasma uridine in a single pass and replaces it largely from hepatic pools of acid-soluble uridine nucleotides. The concentration of uridine in the hepatic vein of the rat was essentially the same as that in the arterial circulation and portal vein. However, the isolated perfused rat liver degraded more than 90 percent of infused [5-3H]uridine in a single passage. Similar results were found in vivo when tracer amounts of [3H]uridine and [14C]uridine were infused into the portal vein of an intact rat. Furthermore, less than 2 percent of the infused uridine entered the acid-soluble nucleotide pools of the liver after 30 minutes of infusion. Intraperitoneal injection of [3H]orotate allowed selective labeling of liver (and kidney) pyrimidines. After 3 hours, the specific activity of uridine in the hepatic vein was more than three times that in the arterial circulation. This unusual exchange, which is not saturated even at uridine concentrations as high as 50 microM, contributes to the rapid turnover of plasma uridine and explains its inefficient utilization in peripheral tissues.