In this study we compared the role of TNF-alpha in the regulation of growth and apoptosis in normal human prostate epithelial cells (NP) and prostate tumor cell lines PC3 and LNCap. The NP and PC3 cells were resistant whereas the LNCap cell line was highly sensitive to TNF-alpha induced growth arrest and apoptosis. The resistance of NP and PC3 cells was mediated via an NF-kB survival pathway as treatment of resistant cells with TNF-alpha was accompanied by phosphorylation of I-kBalpha and translocation of NF-kB to the nucleus. TNF-alpha did not induce phosphorylation of I-kB in the sensitive LNCap cells. The sensitivity of LNCap cells involved a cysteine protease cascade as Z-VAD-CH2 F reversed the sensitivity of LNCap cells and induced resistance to TNF-alpha. The differences in susceptibilities to TNF-alpha induced apoptosis of NP and certain prostate tumor cells offer intriguing possibilities for the treatment of prostate cancer without affecting the normal prostate tissue.