We, and others, have demonstrated that directly reprogramming scar fibroblasts into new cardiomyocytes improves cardiac function in the infarcted heart. A major challenge is the relatively low conversion rate of fibroblasts into cardiomyocytes. We pioneered reprogramming method based on miRNAs, whereby fibroblasts were converted into cardiomyocytes via combination of four miRNAs which we called miR combo. We hypothesized that the efficacy of miR combo could be improved via additional miRNAs. To that end, we screened a number of miRNAs and found that miR-148-3p significantly enhanced the efficacy of miR combo with respect to the expression of cardiomyocyte genes (Actn2, Myh6 and Tnni3; 2 to 5 fold; N=5; P<0.05). Validating a role for miR-148a-3p, addition of the anti-miR-148a-3p inhibited the ability of miR-148a-3p to enhance reprogramming efficacy (N=5, P<0.05). In silico analysis, miR-148a-3p transfection studies, and luciferase reporter assays indicated that Pten, Pik3r3, Rock1 and Mdfic were miR-148a-3p targets. Of these targets, only the overexpression of Mdfic inhibited miR combo (N=4, P<0.05). In contrast, siRNA-mediated knockdown of Mdfic enhanced miR combo efficacy (Actn2, Myh6 and Tnni3; 2 to 10 fold; N=3; P<0.05). These studies suggested that Mdfic was a repressor of the cardiomyocyte phenotype. To provide further evidence, Mdfic mRNA levels were measured in freshly isolated cardiomyocytes and fibroblasts. Mdfic was found to be virtually absent in cardiomyocytes and strongly expressed in fibroblasts (N=3, P<0.05). Moreover, ChIP-qPCR and co-immunoprecipitation analysis indicated that in fibroblasts, Mdfic resided solely on cardiomyocyte genes where it inhibited gene expression by preventing the binding of transcription activator proteins (N=3, P<0.05). In summary, miR-148a-3p improves the efficacy of fibroblast to cardiomyocyte reprogramming via the down-regulation of Mdfic.