T-cell rich, small lymphoid infiltrates of the skin may cause considerable problems in the differential diagnosis of reactive versus neoplastic lymphoproliferations, particularly when they lack the morphologic and immunophenotypical criteria for a malignant lymphoma. We did histologic, immunohistologic, and gene rearrangement studies on 10 biopsies from patients with persistent nodular T-cell-rich skin lesions refractory to topical therapy. Based on clinical and immunohistochemical findings, no discrimination was possible between reactive lesions and malignant lymphoproliferations. Histologically, most of the cases contained T-lymphocytic infiltrations that were assumed to be reactive; however, in four biopsies a neoplastic infiltration could not be excluded. Although the T-cell receptor (TCR) beta chain and the immunoglobulin heavy chain (IgH) genes were in germ-line configuration in nine of 10 cases, indicating a predominantly polyclonal lymphocellular infiltrate, in one patient without clinical evidence of malignant lymphoma at presentation a clonally rearranged TCR beta chain gene with the IgH gene in germ-line configuration was detected. One year later, the patient developed a cutaneous pleomorphic T-cell lymphoma and subsequently a large cell anaplastic (CD30+) T-cell lymphoma in an inguinal lymph node. We conclude that clonal T-cell proliferations can be detected by molecular genetic analysis of T-cell-rich, small lymphoid infiltrates of the skin. This finding may precede development of an overt malignant T-cell lymphoma.