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Direct cardiac reprogramming represents an attractive way to reversing heart damage caused by myocardial infarction because it removes fibroblasts, while also generating new functional cardiomyocytes. Yet, the main hurdle for bringing this technique to the clinic is the lack of efficacy with current reprogramming protocols. Here, we describe our unexpected discovery that DMSO is capable of significantly augmenting direct cardiac reprogramming in vitro. Upon induction with cardiac transcription factors- Gata4 , Hand2 , Mef2c and Tbx5 (GHMT), the treatment of mouse embryonic fibroblasts (MEFs) with 1% DMSO induced ~5 fold increase in Myh6 -mCherry+ cells, and significantly upregulated global expression of cardiac genes, including Myh6 , Ttn , Nppa , Myh7 and Ryr2. RNA-seq confirmed upregulation of cardiac gene programmes and downregulation of extracellular matrix-related genes. Treatment of TGF-β1, DMSO, or SB431542, and the combination thereof, revealed that DMSO most likely targets a separate but parallel pathway other than TGF-β signalling. Subsequent experiments using small molecule screening revealed that DMSO enhances direct cardiac reprogramming through inhibition of the CBP/p300 bromodomain, and not its acetyltransferase property. In conclusion, our work points to a direct molecular target of DMSO, which can be used for augmenting GHMT-induced direct cardiac reprogramming and possibly other cell fate conversion processes. [Display omitted] • DMSO enhances direct reprogramming of mouse embryonic fibroblasts to cardiomyocytes. • CBP/p300 bromodomain inhibition recapitulates the enhancement effect of DMSO. • High transcriptomic concordance exists between DMSO and CBP/p300 bromodomain inhibition. • CBP/p300 HAT domain inhibition failed to enhance direct cardiac reprogramming. • Enhancement effect by DMSO is additive to TGF-β signalling inhibition. [ABSTRACT FROM AUTHOR]