Y-box binding protein 1 (YB-1) functions as a translational regulator and has been suggested to elevate MYC mRNA translation via an internal ribosome entry segment (IRES) point mutation in multiple myeloma (MM). We show that YB-1-mediated translation of MYC mRNA occurs independently of the reported IRES mutation, as 87 MM patients (n=88) and all tested human MM cell lines (HMCLs) were negative for the mutation. We show for the first time that positive MYC staining predicts YB-1 co-expression in malignant plasma cells and YB-1/MYC co-expression increases from 30% in medullary to 70% in extramedullary MM. YB-1 knockdown in HMCLs reduced both MYC protein levels and MYC mRNA in the polysomal fraction, providing a mechanism by which YB-1 controls MYC translation. MYC transcription of YB-1 is demonstrated in HMCLs as MYC knockdown resulted in reduced YB-1 protein and mRNA levels. Furthermore, MYC activation in non-malignant mouse embryonic fibroblasts (MEFs) increased YB-1 mRNA, clearly indicating that MYC drives YB-1 transcription. Importantly, perturbation of the MYC/YB-1 oncogenic circuit leads to apoptosis in HMCLs. Here, we demonstrate that these two proteins co-regulate each other via combined transcriptional/translational activity establishing their pivotal role in MM cell survival. We therefore suggest that targeting the YB-1/mRNA interaction provides a new strategy for MM drug development.