Large cell transformation (LCT) in cutaneous T-cell lymphoma (CTCL) is estimated to occur up to approximately 20% of patients. This morphologic change is associated with aggressive behavior and shortened survival. Our purpose was to identify morphologic and/or immunophenotypic features in CTCL skin biopsies that are predictive of transformation. We analyzed 12 cases of CTCL (three cases of mycosis fungoides and nine cases of Sezary syndrome) that underwent LCT and for which sequential biopsies before and after transformation were available. Eight of 12 cases had pre-LCT marker studies performed on frozen tissue. The histologic and immunophenotypic features of CTCL and LCT were reviewed. Morphologically, CTCL biopsies showed the following: Pautrier microabscesses (five cases), epidermotropism of single lymphoid cells (three cases), and nonspecific histology (four cases). Immunophenotyping prior to transformation showed aberrant loss of T-cell markers (CD5, CD7, CD5 and CD7) in three of eight cases. CD4:CD8 ratios were increased in all cases. Expression of CD25 by the neoplastic lymphoid cells was detected in six of seven cases. LCT immunophenotyping showed additional loss of CD7 in one of five cases and of CD25 in three of five cases. In conclusion, expression of CD25 in CTCL may identify a subset of patients at risk of undergoing LCT.