Scleroderma represents a wide spectrum of disorders ranging from localized patches (morphea) and streaks (linear) to the generalized form, also called systemic sclerosis (SSc), which itself may be of limited or diffuse type and may vary substantially in extent and rate of progression (1, 2). At least 3 areas of pathobiology are perturbed in SSc: immune (autoimmune), vascular/microvascular (endothelial), and fibrotic (fibroblasts and the extracellular matrix [ECM]). Bringing these 3 pathologies together into a unified etiologic framework has been difficult (3). Taken separately, each of the three shares features with other disorders: 1) the immune abnormalities (increased levels of CD4 and Thl, and decreased levels of CD8 T cells in peripheral blood) are similar to those in other autoimmune disorders (rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosus, and Sjogren’s syndrome)(4); 2) the endothelial dysfunction is similar to that in allograft rejection vasculopathy, graft-versus-host disease, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura (3); and 3) the fibroblast activation (increased ECM and membrane adhesion molecule expression, unresponsiveness to growth factors) mimics chronic graft-versushost reaction, porphyrias, and other examples of unregulated scar tissue formation (5). How do these apparently disparate pathologies mesh? We propose that latent human cytomegalovirus (HCMV) infection and its downstream effects on immune, vascular, and repair mechanisms could serve as an accelerating factor in the observed abnormalities of SSc,