Cell fusion can occur between mesenchymal stem cells (MSCs) transplanted to improve cardiac function and cells of the recipient. The therapeutic benefit or detriment of resultant cell hybrids is unknown. Here we augment fusion of transplanted MSCs with recipient cardiac cell types via viral fusogens to determine how cardiac function is impacted. Using a Cre/LoxP-based luciferase reporter system coupled to biophotonic imaging and echocardiography, we found that augmenting fusion with the vesicular stomatitis virus glycoprotein (VSVG) increased the amount of fusion in the recipient mouse heart, but led to diminished cardiac function. Specifically, MSCs transfected with VSVG (MSC-VSVG) had the lowest mean fold increase in fractional area change (FAC) and cardiac output (CO). Although the amount of fusion detected had a strong positive correlation (Pearson) with fractional area change and cardiac output at day 7, this effect was lost by day 28. The decrease in cardiac function seen with MSC-VSVG treatment versus MSC alone or sham treatment was associated with decreased MSC retention, altered immune cell responsiveness and reduced vascularization in the heart. This outcome garners consideration in the context of cellular transplantation to damaged tissues, those with viral infection or other microenvironmental conditions that might promote fusion.