Although studies done in tissue culture (in vitro) have shown synergism between recombinant human tumor necrosis factor (rhTNF) and chemotherapeutic agents, whether such synergism exists in a complex in vivo environment with acceptable toxic side effects has not been determined, to our knowledge. The effect of rhTNF alone and in combination with cisplatin, etoposide, doxorubicin, or dactinomycin on the growth of heterotransplants of human bladder transitional cell carcinoma was studied using a modified subrenal capsule assay in athymic nude mice. Only etoposide potentiated rhTNF cytotoxicity; no increase in host toxicity was noted. Variably enhanced toxic side effects were seen with other combinations. It is concluded that rhTNF combined with etoposide may have potential clinically exploitable therapeutic "synergism" in the treatment of advanced bladder cancer.