The strengths and weaknesses of various laboratory methods for peripheral blood (PB) Sézary cell quantitation have not been compared rigorously. In this study, manual Sézary cell counting, qualitative and quantitative flow cytometry, T-cell receptor (TCR) Vbeta flow cytometry, and TCR polymerase chain reaction were performed on PB specimens from 11 patients with Sézary syndrome (SS), 9 with reactive erythroderma, 6 with mycosis fungoides, and 11 healthy control subjects. These methods identified neoplastic cells in more than 90% of SS cases. The diagnostic specificities of these tests varied; they were enhanced by applying criteria proposed by the International Society for Cutaneous Lymphoma. Comparison of sequentially analyzed specimens from 6 patients with SS revealed that although the absolute number of clonal cells was reduced, in some cases, these cells still constituted the vast majority of the CD4+ T-cell subset, suggesting that quantitative subset analysis might be sufficient to monitor changes in the PB tumor burden.