The lymphatic transport of recombinant human tumor necrosis factor (rHu-TNF) was investigated after its administration via various routes in anesthetized rats. After intravenous (i.v.) administration, the level of rHu-TNF in the lymph reached a peak at 2 h, and thereafter decreased exponentially in a pattern similar to that of the elimination from plasma. Intramuscular (i.m.) and subcutaneous (s.c.) administrations resulted in low levels of rHu-TNF both in the plasma and in the lymph. On the other hand, intraperitoneal (i.p.), intra-stomach wall (s.w.) and intra-gut wall (g.w.) administrations gave high lymph levels of rHu-TNF. After the s.w., g.w. and i.p. administrations, the ratios of rHu-TNF recovered from the thoracic duct to the cumulative amount estimated from the rHu-TNF concentration in plasma were about 25, 32 and 8 times higher than in the case of i.v. administration, respectively. These results suggest that the routes of local administration of rHu-TNF such as s.w., g.w. and i.p. may be highly effective for the treatment of lymphatic metastasis of cancer.