Systemically administered tumour necrosis factor (TNF) has anti-tumour effects in animal tumour models but its clinical application is limited by severe toxicity. Interferon-gamma(IFN-gamma) has been shown to augment the anti-tumour effect of TNF. We evaluated the effect of paralesional (p.I.) injections of TNF plus IFN-gamma in a murine tumour model and compared the toxicity and anti-tumour effect with that seen with systemic administration. C57BL6 mice with 10-day subcutaneous MCA sarcomas were treated with daily p.I. injections of recombinant huTNF +/- IFN-gamma for 5 days. Optimal mean survival and 30-day cure rate was seen with doses of 5 micrograms TNF-alpha + 5000 U IFN-gamma (P < 0.05 vs. control or IFN-gamma alone). Tumour response after a single i.v. injection of 0-15 micrograms TNF + 5000 U IFN-gamma was then compared with five daily p.I. injections of the same dose of TNF-alpha and IFN-gamma. All animals with p.I. injections of > 5 micrograms TNF had initial complete necrosis of tumour with a variable degree of surrounding tissue necrosis, with rapid regrowth of tumour seen in some animals. Although treatment-related mortality was similar between i.v. and p.I. therapy, there was a higher percentage of animals cured with p.I. injections with overall cure rates in treated animals at 30 days of 17% vs. 72% (i.v. vs. p.I., P < 0.01) and 13% vs. 67% (P < 0.04) in a repeat study. 2+ clinical applications.