A multi-subunit exosome complex is a major eukaryotic exoribonuclease that in the cytoplasm requires the SKI complex for activity. In yeast, SKI forms a heterotetramer and delivers RNA substrates directly into the exosome channel. Such cooperation requires Ski7 protein, which links the exosome and SKI complexes. However, since the human genome does not encode an orthologue of the yeast Ski7, the factor mediating SKI and exosome linkage in human cells is unknown. Proteomic analysis revealed that the human cytoplasmic exosome interacts with HBS1LV3, a protein encoded by a newly discovered short splicing isoform of HBS1L. HBS1LV3 recruits the SKI complex to the exosome. In contrast, the canonical HBS1L variant, HBS1LV1, acting as a ribosome dissociation factor, does not associate with the exosome and instead interacts with the mRNA surveillance factor PELOTA. HBS1LV3 contains a new domain of unknown structure with the short linear motif RxxxFxxxL, which is responsible for exosome binding, and may interact with the exosome core subunit RRP43 in way that resembles the association between Rrp6 RNase and Rrp43 in yeast. Depletion of HBS1LV3 and the SKI complex helicase SKI2W similarly affected the transcriptome by strongly upregulating a large number of genes. Moreover, following HBS1LV3 or SKI2W depletion the half-lives of representative upregulated mRNAs were increased, thus supporting the involvement of HBS1LV3 and SKI2W in the same mRNA degradation pathway. In contrast, HBS1LV1 depletion had little effect on transcriptome homeostasis. Our data indicate that human HBS1LV3 is the long-sought factor that links the exosome and SKI complexes to regulate cytoplasmic mRNA decay. Overall design: Examination of siRNA-mediated silencing in HEK293 cell lines. To identify transcripts that are degraded by cytoplasmic SKI/HBS1LV3/exosome supercomplexes, we used specific siRNAs to knock down HBS1LV1, HBS1LV3 or SKIV2L gene expression in (i) WT HEK293 cells and (ii) HEK293 cells rescued with siRNA insensitive protein. Analyses were performed in triplicate.