Introduction: Duchenne muscular dystrophy is a severe muscle wasting disease caused by the lack of dystrophin expression. Patients die of heart failure in their second or third decade of life. Delivery of full-length dystrophin is not practical due to the large size of the gene; however, smaller variants of dystrophin, called microdystrophins, have shown promise in restoring function to the skeletal muscle. These microdystrophins are currently being dosed to patients in clinical trials; however, therapeutic efficacy in the heart is unknown due to challenges in modeling DMD-associated heart failure in animal models. Hypothesis: We hypothesized that microdystrophin gene therapy can ameliorate disease phenotypes in DMD iPSC-cardiomyocytes. Methods: This study uses human induced pluripotent stem cells (iPSCs) to model the functional deficits of cardiomyocytes. By comparing DMD cells with isogenic controls where the dystrophin mutations are corrected, we are able to focus on disease phenotypes attributed to the disease in vitro. We performed viability assays to assess cell survival, ratiometric calcium imaging to evaluate calcium handling, and traction force microscopy to measure the force of contraction. Results: We found that iPSC-cardiomyocytes exhibit poor viability, aberrant calcium handling, and reduced force of contraction. When we delivered three microdystrophin variants to DMD iPSC-cardiomyocytes, we found the microdystrophins improved cell viability and partially rescued functional deficits. Conclusions: These findings demonstrate that this platform can be used to test the therapeutic efficacy of dystrophin variants in the molecular context of human cells.