Introduction: Co-culturing human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiCMs) with other stem/progenitor cells like bone-marrow mesenchymal stem cells (BM-MSCs) and endothelial progenitors has been shown to improve their survival post transplantation into ischemic hearts. Co-culturing with other cardiac cells has also shown to improve the maturation of hiCMs in vitro. However, the potential of co-culturing hiPSC-derived MSCs (hiMSCs) for hiCM maturation and cardioprotection has not been explored. Hypothesis: We hypothesize that co-culturing of hiMSCs with hiCMs significantly alters the cells’ proteome, improves hiCM maturation, and enhances cardioprotection. Results: hiCMs were co-cultured with hiMSCs for one week at a ratio of 3:1. To evaluate the effect of hiMSCs on hiCM maturation in the co-culture, changes in the hiCM function and gene expression were assessed via multi electrode array (MEA) analysis and qPCR, respectively. MEA analysis showed an increase in ADP50 and ADP90 in addition to improved response to cardiac drugs in hiCMs co-cultured with hiMSCs as compared to hiCM-only cultures, indicating improved maturation of hiCMs in the co-culture. Furthermore, gene expression analysis showed an increased expression of mature CM-associated genes (MYH7, TNNT2). When subjected to hypoxic stress (1% O 2 ), we also observed a significant decrease in the number of TUNEL positive cells in the co-cultures as compared to hiCM-only culture. Assessment of hiCM functionality via MEA analysis showed an improved cardioprotection in co-cultures as compared to the single cell-type cultures. Furthermore, proteomic analysis demonstrated increased expression of cardioprotective growth factors (GFs): HGF, VEGFA and IGFBP-1 in the conditioned medium of the co-cultured cells versus single cell-type cultures. Conclusion: Overall, our results established that co-culturing hiCMs with hiMSCs improved cardioprotection via increased the expression of cardioprotective growth factors and enhanced the maturation of hiCMs in vitro.