Repetitive administration of low doses of tumor necrosis factor (TNF) results in a state of selective tolerance to some of its effects. We have demonstrated that tolerance does not impair the therapeutic efficacy of TNF against a syngeneic murine B16BL6 melanoma and allows a complete cure. Another study, performed with a distinct tumor model, came to apparently contradictory results. To clarify this, we investigated whether the outcome depended on the tumor type and on the inclusion of interferon‐γ (IFNγ) in the treatment. Three syngeneic tumors of different histological origin, i.e., B16BL6 melanoma, Lewis lung carcinoma (LLC) and EL4 lymphoma, were compared in C57BL/6 mice. The anti‐tumor efficacy of TNF against BI6BL6 and EL4 was not impaired in tolerant mice, but the effect of TNF against LLC was slightly, though significantly, reduced. Inclusion of IFNγ in the treatment regimen, however, abolished this difference and resulted in complete cure for all 3 tumor systems. As therapeutically optimal doses were lethal in normal mice, only tolerance allowed a long‐term cure. We conclude that the influence of tolerance on the anti‐tumor activity of TNF as a single agent depends on the tumor type; in combination therapy with IFNγ, however, tolerance allowed us to dissociate lethal toxicity from anti‐tumor activity, irrespective of the tumor type tested. © 1995 Wiley‐Liss, Inc.