IL-17 is a recently identified proinflammatory cytokine that plays pivotal roles in several chronic inflammatory disease models. Its expression was also found to be elevated in the serum of patients with chronic diseases. However, whether elevated systemic IL-17 expression can induce pathophysiological tissue inflammation is unknown. In this study, we demonstrated that systemic overexpression of IL-17 using an adenoviral vector could induce multiple tissue inflammation and wasting in mice. We also found that the expression of TLR4 was increased in tissues of IL-17-overexpressing mice. Moreover, TLR4 activation is required for IL-17-induced tissue inflammation and wasting, as evidenced by the absence of aggressive atrophy in gastrocnemius muscle, neutrophil accumulation, and expression of proinflammatory cytokines downstream of TLR4 in multiple tissues of TLR4-deficient mice. Further investigation revealed that TLR4 endogenous ligands high-mobility group box 1 and heat shock protein 22, were systemically upregulated and might be involved in the IL-17-induced TLR4 activation. Our results suggest that IL-17 may induce disease-associated tissue inflammation and wasting through TLR4 signaling. The study indicates a novel interaction between IL-17 and TLR4 activation and may have implications in the pathogenesis and treatment of chronic diseases.