Psoriasis is a complex inflammatory skin disease in which local vascular changes, T-cell activation, abnormal keratinocyte proliferation and differentiation, and neutrophil activation all contribute to the ongoing disease process. Because of recent interest in T-cell activation as a trigger for psoriatic lesions, we hypothesized that psoriasis may be triggered by superantigens, e.g., toxins of microbial origin that stimulate T cells expressing particular T-cell receptor (TCR) β chain variable (Vβ) gene segments. Lesional skin biopsies and peripheral blood from two patients with acute exacerbations of their psoriasis that appeared to be triggered by infection were analyzed for TCR Vβ gene expression using monoclonal antibodies directed against Vβ 5.1, 5.2, 6.7, 8.1, and 12. Skin biopsies from both patients demonstrated a different pattern of Vβ expansion that corresponded to the Vβ pattern expected to be induced by the type of superantigen expressed during the infection. In contrast, using immunofluorescence and flow cytometry, peripheral blood T cells from these patients did not demonstrate any expansion of the 5 Vβ subsets studied. These observations support the hypothesis that local activation of cutaneous T cells in psoriasis may be caused by a superantigen and provides a new direction for investigating the pathogenesis of this complex and fascinating skin disorder.