Abstract. We have investigated the effect of interferon (INF) on the natural killer (NK) cytotoxic activity of peripheral blood mononuclear cells (PBMC) from patients with superficial and infiltrative transitional-cell carcinoma of the bladder (TCC) against both NK-sensitive and NK-resistant target cells. The normal NK activity found in PBMC from these patients can be significantly enhanced by short-term incubation (18 h) with INF (P 0.05). The depressed NK cytotoxic activity found in PBMC from patients with infiltrative TCC can also be significantly enhanced, but not normalized, by short-term incubation with INF (P 0.05). In kinetic studies we found that the maximal levels of the INF-promoted cytotoxic activity against NK-sensitive and against NK-resistant target cells in PBMC from TCC patients were reached after 18 h of culture. Short-term-INF-incubated PBMC from patients with TCC of the bladder also showed marked cytotoxic activity against NK-resistant target cells. The effector cells of the INF-induced cytotoxic activity in PBMC from patients with TCC were CD16+ CD3 NK cells. This cytotoxic inducer effect of INF synergized with that of interleukin-2. In conclusion, INF can enhance the NK activity of PMBC from patients with TCC of the bladder.