Interleukin-17A (IL-17A) is increased in systemic sclerosis (SSc) skin and other organs but its role in disease pathogenesis is debated. Since epithelial cells are preferential targets of IL-17A, we aimed at investigating the role of IL-17A in the interactions between epidermis and dermis in the settings of skin fibrosis. We uncovered an unexpected synergic activity of IL-17A with transforming growth factor-β (TGF-β), the master pro-fibrotic cytokine, resulting in an enhanced production of IL-6 by fibroblasts, driven by p38 MAPK signaling pathway. Simultaneously, we observed a decreased type I collagen production associated with reduced SMAD phosphorylation. In skin explants and in keratinocyte-fibroblast interactions model IL-17A not only decreased extracellular matrix deposition by itself, but also counteracted TGF-β pro-fibrotic activities. These data point to pro-inflammatory and anti-fibrotic properties of IL-17A and may help in directing and interpreting therapeutic approaches in SSc, since IL-17A, TGF-β, and IL-6 are target candidates in clinical trials.