The objective of this study was to determine the effect on lymphocyte traffic of the long-term administration of prostaglandins to peripheral lymph nodes of sheep in vivo. In 12 studies prostaglandin E2 (PGE2) was infused continuously by digital syringe pump into cannulated afferent lymphatics of nine popliteal lymph nodes in eight sheep. In 32 studies, arachidonic acid emulsified in sterile autologous serum or lymph was injected subcutaneously into the drainage area of peripheral lymph nodes in 11 sheep. Lymphocyte traffic was monitored by the output of small and blast lymphocytes into efferent lymph, which was collected by long-term cannulation. Long-term infusion of PGE2 produced a sustained decrease in the output of small lymphocytes in all of 12 studies and a decrease in blast cell output in all of the six infusions in which blast cell output was elevated prior to infusion. Cessation in PGE2 infusion was associated with increase in the output of small and blast lymphocytes into afferent lymph in all of eight studies. Single or repeated depot-type emulsion injections of arachidonic acid in amounts of 20 mg or more depressed small lymphocyte output in all of 30 studies, and injections of 0.2 mg or more depressed blast lymphocyte output in all of 22 studies in which blast cell outputs were elevated prior to the initial injection. It is observed that long-term bombardment of peripheral lymph nodes of sheep in vivo with prostaglandins, primarily of the E series, produces a chronic depression in lymphocyte traffic as mirrored in the output of small and blast cells into efferent lymph. We suggest that this response may be one of several mechanisms by which prostaglandins may affect the immune response in vivo.