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Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) have attracted attention as a novel tool for drug safety screening and several differentiation protocols of hiPSC lines into cardiomyocytes have been reported; the standardization of these protocols will expand their applications for safety assessments such as "clinical safety trial-on-dish". Bone morphogenetic protein 4 (BMP4) is an important factor in promoting mesoderm differentiation and BMP4 treatment has been used at the early stage of cardiac differentiation into different hiPSCs. In the present study, we evaluated the effects of BMP4 treatment at the early stage of cardiac differentiation. We performed gene expression profiling of the germ layer during mesoderm differentiation of hiPSCs derived from three different donors. The expression of T (a mesoderm marker) and GATA6 (an endoderm marker) increased and that of PAX6 (a neuroectoderm marker) decreased in pooled embryoid bodies (EBs) after BMP4 treatment. Single-cell gene expression analysis revealed that mesodermal and mesendodermal populations increased in EBs derived from 253G1. Finally, BMP4 treatment increased mesodermal and mesendodermal populations compared with that without BMP4 in two other hiPSC lines, confirming the reproducibility of multiple hiPSC lines. Thus, our results suggest that BMP4 treatment increases mesodermal and mesendodermal populations at the early stage of cardiac differentiation in different hiPSC lines., Competing Interests: All authors are full-time employees of Takeda Pharmaceutical Company Limited and this study was fully sponsored by Takeda., (Copyright © Journal of Stem Cells and Regenerative Medicine.)