Previous studies have demonstrated that the chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 8 (CMTM8) protein accelerates the ligand-induced clearance of epidermal growth factor receptor (EGFR) from the cell surface. The absence of EGFR-mediated signaling induces cells to undergo apoptosis via caspase-dependent and -independent pathways. Here we report the cloning and sequencing of an alternative splice form of CMTM8, obtained from a human blood cDNA library, that utilizes apoptotic pathways distinct from CMTM8. The alternative splice variant arises from a deletion of exon 2 that prevents the expression of a full-length MARVEL domain, and cytosolic YXXΦ motifs. Nevertheless, CMTM8-v2 maintains the ability to induce apoptosis via caspase-dependent and -independent pathways to inhibit cell growth and colony formation. CMTM8 and CMTM8-v2 display different expression profiles and distinct subcellular localization patterns, while operating via different mechanisms to induce apoptosis. CMTM8-v2 did not affect EGFR internalization, implying that the MARVEL domain and/or the cytosolic YXXΦ motifs are necessary for CMTM8 to accelerate ligand-induced EGFR internalization. © 2007.