Abstract The effect of propanil on mouse peritoneal macrophages (mφ) was measured by determining cytotoxicity via the P815 cell line, which is resistant to tumor necrosis factor α (TNF-α). Although control animals showed a typical pattern of requiring both interferon (IFN)-γ and lipopolysaccharide (LPS) for mφ activation, mφ from propanil-treated animals were cytotoxic when induced with LPS alone. This suggested that propanil influenced endogenous IFN levels. This was confirmed by the abrogation of cytotoxicity upon addition of anti-IFN to the cultures. When cells were assayed for IFN transcript, mRNA in resident mφ was present in higher concentrations in propanil-treated animals. IFN mRNA was present in even higher concentrations in mφ from propanil-treated animals after 30 mm of culture with LPS, whereas control mφ required 4 hr in culture with [PS to produce similar levels. IFN protein levels were also higher in propanil-treated mφ after culture in the presence of LPS. Thus, propanil induces increased levels of endogenous IFN which probably works in conjunction with LPS to induce P815 cytotoxicity. Because of the known influence IFN has on the increased secretion of TNF-α, we tested the tumoricidal activity of mφ from propanil-treated animals against TNF-α-sensitive cell lines. When using WEHI-TI-164 or [929 cells, mφ from propanil-treated animals revealed tumoricidal activity with just the addition of LPS or IFN-γ. This implies that the additional endogenous levels of IFN, combined with other propanil-induced effects, caused increased secretion of TNF-α from mφ.