Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets. Here, we report that VPS4B gene, encoding an ATPase involved in ESCRT‐dependent membrane remodeling, is such a passenger gene frequently deleted in many cancer types, notably in colorectal cancer (CRC). We observed downregulation of VPS4B mRNA and protein levels from CRC patient samples. We identified VPS4A paralog as a synthetic lethal interactor for VPS4B in vitro and in mouse xenografts. Depleting both proteins profoundly altered the cellular transcriptome and induced cell death accompanied by the release of immunomodulatory molecules that mediate inflammatory and anti‐tumor responses. Our results identify a pair of novel druggable targets for personalized oncology and provide a rationale to develop VPS4 inhibitors for precision therapy of VPS4B‐deficient cancers. Synopsis VPS4B and VPS4A paralogs are involved in the remodeling of biological membranes, a critical step for many intracellular processes. This study highlights the possibility of using synthetic lethality between these paralogs for treatment of VPS4B‐deficient cancers. VPS4B protein abundance was decreased in colorectal cancer (CRC) patient samples. A synthetic lethal phenotype was generated by simultaneous depletion of VPS4A and B in various CRC cell lines grown in vitro and in vivo. Synthetic lethality between VPS4A and B was independent of other oncogenic mutations, and conserved between human and mouse, thus of high penetrance. Simultaneous depletion of VPS4A and B caused pleiotropic effects e.g. inhibited endocytosis and cell cycle progression, and induced a stress‐associated sterile inflammatory response. DAMPs and other immunomodulatory molecules released by VPS4A+B‐depleted dying cells may favor the induction of anti‐tumor innate and adaptive immune responses. VPS4B and VPS4A paralogs are involved in the remodeling of biological membranes, a critical step for many intracellular processes. This study highlights the possibility of using synthetic lethality between these paralogs for treatment of VPS4B‐deficient cancers.