Molecular genetic T-cell receptor (TCR) and flow cytometric analysis using antibodies to conventional T-cell antigens and TCR beta-chain variable region families (TCR-Vbeta) were performed in 65 peripheral blood specimens evaluated for potential involvement by a T-cell lymphoproliferative disorder (TCLPD). A normal or reactive conventional T-cell immunophenotype was present in 36 cases; TCR-Vbeta flow cytometric and molecular TCR analyses were negative for clonality in 32 and 27 of these cases, respectively. In the remaining normal and reactive cases, one or both methods seemed to detect dominant cell populations in settings with limited T-cell diversity. We identified 29 TCLPDs; all studied cases had clonal molecular TCR results; 23 TCLPDs had clonal TCR-Vbeta flow cytometric results; the remaining were suggestive of (n = 3) or negative (n = 3) for clonality. TCR-Vbeta flow cytometric analysis is a powerful clinical laboratory tool that can be used to aid in the rapid diagnosis of peripheral blood involvement by T-cell malignant neoplasms.