Interleukin-6 (IL-6) is a pleiotropic cytokine responsible for many different processes including the regulation of cell growth, apoptosis, differentiation and survival in various cell types and organs, including the heart. Recent studies have indicated that IL-6 is a critical component in the cell-cell communication between myocytes and cardiac fibroblasts. In this study, we examine the effects of IL-6-deficiency on the cardiac cell populations, cardiac function and interactions between the cells of the heart, specifically cardiac fibroblasts and myocytes. To examine the effects of IL-6-loss on cardiac function, we used the IL-6^-/- mouse. IL-6-deficiency caused severe cardiac dilatation, increased accumulation of interstitial collagen and altered expression of the adhesion protein periostin. In addition, flow cytometric analyses demonstrated dramatic alterations in the cardiac cell populations of IL-6^-/- mice when compared to wild type littermates. We observed a marked increase in the cardiac fibroblast population in IL-6^-/- mice, while a concommitment decrease was observed in the other cardiac cell populations examined. Moreover, we observed increased cell proliferation and apoptosis in the developing IL-6^-/- heart. Additionally, we observed a significant decrease in the capillary density of IL-6^-/- hearts. In order to elucidate the role of IL-6 in the interactions between cardiac fibroblasts and myocytes, we performed in vitro studies and demonstrated that IL-6-deficiency attenuated activation of the STAT3 pathway and VEGF production. Taken together, these data demonstrate that loss of IL-6 causes cardiac dysfunction by shifting the cardiac cell populations, altering the extracellular matrix, and disrupting critical cell-cell interactions.