One of the hallmarks of chronic cardiac disease is the excessive formation of fibrous extracellular matrix. This inappropriate remodeling is mediated in large part by cardiac fibroblasts and phenoconverted myofibroblasts. The protooncoprotein Ski has previously been described as possessing anti-fibrotic properties within the myocardium, in addition to triggering apoptosis when overexpressed. In the current study, we found that overexpression of Ski results in a set of distinct morphological and biochemical changes within primary cardiac myofibroblasts that is indicative of apoptosis. Its upregulation is associated with the expression of pro-apoptotic factors such as Bax and Bak, as well as caspase-9 and -7. In all, our results indicate that Ski triggers a pro-death mechanism in primary rat cardiac myofibroblasts that is mediated through the intrinsic apoptotic pathway. The survival of these cells appears to be prolonged by a pro-survival autophagic response as apoptosis is hastened when autophagy is inhibited. The observed cell death response is likely working in parallel with the previously observed anti-fibrotic properties of Ski within this cell type. As myofibroblast cells are the engines of matrix expansion in heart failure, we suggest that using Ski or a projected Ski-mimetic to induce graded apoptosis in myofibroblasts within the failing heart may be a novel therapeutic mechanism of controlling cardiac fibrosis.