Differentiation between Sezary's syndrome (SS) and benign forms of erythroderma may be extremely difficult. In this study T-cell receptor beta (TCR-beta) gene rearrangement analysis was performed on peripheral blood lymphocytes (PBL) from 32 patients with erythroderma, including 10 patients with SS, three patients with another type of cutaneous T-cell lymphoma, and 19 patients with a benign form of erythroderma. The aim of this study was to define the sensitivity and specificity of this technique in the diagnosis of SS. Clonal TCR-beta gene rearrangements were found in eight of 10 patients with SS, one T-CLL patient, one of two patients with erythrodermic mycosis fungoides, and only one of 19 patients from the benign group. In the two "false-negative" cases of SS clonal TCR-beta gene rearrangements were detected in PBL obtained during follow-up. The results indicate that TCR-beta gene rearrangement analysis on PBL is a sensitive and highly specific technique, that may contribute significantly to the differential diagnosis of patients with erythroderma. However, because both "false-positive" and "false-negative" results may occur, the results of gene-rearrangement analysis should always be considered in conjunction with clinical, histologic, and immunophenotypical data.