Among the many immunomodulatory and anti-tumor activities,IFN-γ up-regulates tumor cell death mediated by Fasreceptor(FasR). Our and several other studies have demonstrated the involvement of trypsin-likeproteases(TLPs)in the mode of action of IFN-γ. In the present study,we tried to unravel the role of serine proteases in IFN-γ induced Fas-mediated cell death.Our present results show that bothtosyl-L-Lysinechloromethylketone (TLCK) ,atrypsin like protease inhibitor and tosyl-L-phenyla- laninechloromethylketone(TPCK) – a chymotrypsinlikeprotease(CLP)inhibitor,sensitizeHeLacellsto Fas-mediatedcelldeath.Thecombinedeffectoftheseproteaseinhibitors with anti-Fas was stronger than additive. Incontrast, elastaseinhibitorIII(EI) ,which also contains thechloromethyl ketone moiety, was not active.Furthermore,co-addition ofTLCK or TPCK with IFN-γ markedlyenhanced Fas- induced cell death. IFN-γ ledtoup-regulation of Fas R on itsown, which was further enhanced by the co-addition of TLCKorTPCK. This was evident both by increased expression of Fas receptor on cell surface and by elevated FasmRNAlevel. This study may provide the basis for the design of anovel combinatory therapeutic strategy that could enhance the eradication of tumors.