Tenascins are a family of large multimetric extracellular matrix (ECM) proteins. Among them, large molecular weight variant tenascin-C is known to be specifically expressed in pathological conditions. However, no link between tenascin-C and collagen diseases has been established. The aim of our study was to determine the serum tenascin-C levels in patients with various collagen diseases, and to evaluate the possibility that serum levels of tenascin-C can be a useful marker for collagen diseases, correlating with the pathogenesis. Serum tenascin-C levels of 33 patients with scleroderma (SSc), 10 patients with scleroderma spectrum disorder (SSD), 15 patients with localized scleroderma (LSc), 12 patients with dermatomyositis (DM), 10 patients with systemic lupus erythematosus (SLE) and 15 healthy controls were measured with specific enzyme-linked immunosorbent assays. Serum tenascin-C levels were significantly elevated in patients with SSc, SSD and LSc than in healthy controls. Significantly higher total skin thickness score or higher incidence of pitting scars/ulcers and diffuse pigmentation were observed in SSc patients with elevated tenascin-C levels than in those with normal levels. Our study suggests that serum tenascin-C levels are increased in fibrotic conditions, and that tenascin-C contributes to the pathogenesis of vascular damage as well as fibrosis in SSc patients. Clarifying the role of tenascin-C in the pathogenesis of collagen diseases may lead to a new therapeutic approach.