Splenic lymphocytes from Fischer rats with carcinogen (FANFT)-induced bladder cancer had depressed natural cytotoxicity that could be enhanced in vitro by the addition of mouse leukocyte interferon to the cytotoxicity assay. Such enhancement appeared to reflect an effect directly on lymphocytes rather than a cytotoxic effect on tumor target cells. The possibility that tumor cell prostaglandin production might partially inhibit lymphocyte cytotoxicity and its enhancement prompted separate attempts to enhance cytotoxicity by inhibiting prostaglandin production during cytotoxicity testing. However, addition of indomethacin to the cytotoxicity assays did not enhance cytotoxicity in lymphocytes from either control or tumor-bearing rats and did not add to the enhancement seen with interferon. Addition to the cytotoxicity assay of unstimulated peritoneal monocytes which themselves have been shown to produce prostaglandins, did not effect lymphocyte cytotoxicity. Correspondingly, indomethacin in parallel samples did not alter baseline levels of cytotoxicity seen. Further stimulation of cytotoxicity by addition of interferon to these samples was also not seen. Taken together, in vitro enhancement of depressed lymphocyte cytotoxicity in tumor-bearing animals was possible with exogenous leukocyte interferon, could not be accomplished by inhibition of prostaglandin production in this system, and did not appear to be influenced by the addition or deletion of monocytes during cytotoxicity testing.