We have isolated Spike, a novel and evolutionary conserved BH3‐only protein. BH3‐only proteins constitute a family of apoptosis inducers that mediate proapoptotic signals. In contrast to most proteins of this family, Spike was not found to be associated with mitochondria. Furthermore, unlike the known BH3‐only proteins, Spike could not interact with all tested Bcl‐2 family members, despite its BH3 domain being necessary for cell killing. Our findings indicate that Spike is localized to the endoplasmic reticulum. The endoplasmic reticulum is an organelle that has only recently been implicated in regulation of apoptosis. At this locale, Spike interacts with Bap31, an adaptor protein for pro‐caspase‐8 and Bcl‐XL. In doing so, Spike is able to inhibit the formation of a complex between Bap31 and the antiapoptotic Bcl‐XL protein. Furthermore, Spike transmits the signal of specific death receptors. Its down‐regulation in certain tumors suggests that Spike may also play a role in tumorigenesis. Our findings add new insight for how BH3‐only and antiapoptotic Bcl‐2 proteins regulate cell death.