Systemic sclerosis (SSc) is a collagen disease characterized by autoimmunity and excessive extracellular matrix deposition in the skin and visceral organs. Although the pathogenic relationship between systemic autoimmunity and the clinical manifestations of SSc remains unknown, SSc patients show a variety of abnormal immune activation including the production of disease-specific autoantibodies and cytokine production. Many recent studies have demonstrated that immune cells, including T cells, B cells, and macrophages, have a variety of immunological abnormalities in SSc. So far, several groups and our group reported that B cells play a critical role in systemic autoimmunity and disease expression through various functions, such as cytokine production, lymphoid organogenesis, and induction of other immune cell activation in addition to autoantibody production. Recent studies show that B cells from SSc patients demonstrate an up-regulated CD19 expression, a crucial regulator of B cell activation, which induces chronic hyper-reactivity of memory B cells and SSc-specific autoantibody production and also causes fibrosis of several organs. Furthermore, in SSc-model mice, such as tight-skin mice, bleomycin-induced SSc model mice, and DNA topoisomerase I and complete Freund's adjuvant-induced SSc model mice, have abnormal B cell activation which associates with skin and lung fibrosis. Indeed, B cell depletion therapy using anti-CD20 Ab, Rituximab, is considered to one potential beneficial treatment for patients with SSc. However, there is no direct evidence which can explain how B cells, especially autoantigen-reactive B cells, progress or regulate disease manifestations of SSc. Collectively, B cell abnormalities in SSc is most likely participating in fibrosis and tissue damage of SSc. If the relationship between SSc-specific tissue damage and B cell abnormalities is revealed, these findings lead to novel effective therapy for SSc.