Abstract The cellular FLICE-inhibitory protein (c-FLIP) is a modulator of death receptor-mediated apoptosis and plays a major role in T- and B-cell homeostasis. Three different isoforms have been described on the protein level, including the long form c-FLIPL as well as 2 short forms, c-FLIPS and the recently identified c-FLIPR. The mechanisms controlling c-FLIP isoform production are largely unknown. Here, we identified by sequence comparison in several mammals that c-FLIPR and not the widely studied c-FLIPS is the evolutionary ancestral short c-FLIP protein. Unexpectedly, the decision for production of either c-FLIPS or c-FLIPR in humans is defined by a single nucleotide polymorphism in a 3′ splice site of the c-FLIP gene (rs10190751A/G). Whereas an intact splice site directs production of c-FLIPS, the splice-dead variant causes production of c-FLIPR. Interestingly, due to differences in protein translation rates, higher amounts of c-FLIPS protein compared with c-FLIPR are produced. Investigation of diverse human cell lines points to an increased frequency of c-FLIPR in transformed B-cell lines. A comparison of 183 patients with follicular lymphoma and 233 population controls revealed an increased lymphoma risk associated with the rs10190751 A genotype causing c-FLIPR expression.