The apoptosis cascade that plays a central role in normal and pathological processes is strictly controlled, in part by FLIP (Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein), an inhibitor of caspase-8. Here, we report the expression of long and short isoforms of FLIP mRNAs and proteins in early and late gestation human placentas, term cytotrophoblast cells and two choriocarcinoma cell lines, JEG-3 and Jar. Reverse transcriptase polymerase chain reaction identified mRNAs derived from the FLIP gene in all samples. Analysis by immunoblotting revealed that both long and short forms of FLIP proteins are present in early and late gestation human placentas with increasing levels over gestation and that FLIP proteins are present in normal and transformed trophoblast cells. Immunohistochemical experiments performed on paraformaldehyde-fixed tissue sections taken from early and late stages of pregnancy demonstrated that FLIP proteins are present in caspase-8-expressing cells and that expression patterns of FLIP differed according to cell lineage and stage of cell differentiation. The results of this study are consistent with the postulate that FLIP proteins have critical roles in placental cell survival and suggest that FLIP may protect normal and transformed trophoblast cells from cell death.