Reed-Sternberg (RS) cells, the neoplastic elements of Hodgkin's lymphoma (HL), usually lack B-cell receptor expression. Normal germinal center B cells, with lack of or low-affinity B-cell receptor expression, are eliminated via FAS-induced apoptosis. RS cells express FAS, but are rescued from apoptosis by a transforming event. It is known that HL-derived cell lines are resistant to FAS-mediated apoptosis. To investigate potential causes for this resistance, FAS mutations and c-FLIP expression were studied in four HL-derived cell lines and 20 cases of HL. L1236 was found to have a splice donor site mutation in intron 7 that resulted in an aberrantly spliced FAS transcript. Screening of microdissected RS cells revealed loss of heterozygosity for a known exon 7 polymorphism in two of six informative cases indicating loss of one FAS allele. In one of the two cases with loss of heterozygosity a hemizygous mutation was detected in exon 9. c-FLIP expression was observed in all HL cell lines and in RS cells of all HL cases. Our data show that FAS mutations are rare and suggest that overexpression of c-FLIP, which was present in all cases, is involved in the resistance to FAS-mediated apoptosis.