Flow cytometry (FC) is frequently used to detect aberrant peripheral blood (PB) T cells ("Sézary cells") in patients with mycosis fungoides (MF) and Sézary syndrome (SS). However, immunophenotypic stability of MF/SS over time is not well characterized. We analyzed 141 PB samples from 9 cases (2 SS, 7 MF). At diagnosis, there were 3 to 5 immunophenotypic aberrancies per case (median, 4), including dim or absent CD2, CD3, CD4, CD5, CD7, or CD26 and bright CD45RO. Of 9 patients, 7 had a subsequent change in immunophenotype. All patients retained multiple aberrancies at follow-up (median, 3 per analysis; range, 2-6), of which 22.0% (81/369) were new. In 5 patients, a more than 99% decrease in absolute Sézary cell (ASC) counts by FC after alemtuzumab therapy or total skin electron beam radiation was associated with clinical improvement. We observed minor immunophenotypic changes over time in most patients with MF/SS; however, the Sézary clones maintain persistently aberrant immunophenotypes and seem amenable to follow-up with limited FC panels. ASC counts by FC correlated well with clinical response.