Adult T-cell leukemia/lymphoma (ATLL) is caused by the HTLV-1 virus, endemic to Japan and the Caribbean, and is likely derived from cells with the T-regulatory phenotype. The malignant cells express IL2 receptor α (CD25), and the majority express transcription factor Forkhead box P3 (Foxp3), in addition to T-cell markers. Occasional cases express CD30. Whereas Japanese cases are predominantly of the acute and chronic leukemic types, the less well-studied Caribbean cases are more often lymphomatous. We performed immunohistochemical analysis for CD25, Foxp3, and CD30 on samples from 42 US/Caribbean ATLL patients and correlated these markers with morphologic subtype and clinical characteristics. In the 16/42 patients who had successive biopsies, we determined the expression stability of these markers. Foxp3 was expressed in 26 of the 42 (62%) initial biopsies, and its intensity correlated with CD25 expression. It was more frequent in pleomorphic small-sized and medium-sized cell types than in large cell tumors but did not correlate with patients' clinical attributes. Foxp3 expression and morphology were unchanged in successive biopsies in 13 of 16 patients. Four initial biopsies had features of anaplastic large cell T lymphomas, all of which were Foxp3. Successive biopsies from 2 patients with pleomorphic medium cell variant showed diminishing expression of originally weak Foxp3 expression and de novo CD30 expression, whereas they showed morphologic progression to the anaplastic cell variant. A third patient's second biopsy revealed progression from pleomorphic medium to anaplastic large cell morphology with loss of Foxp3, but it remained CD30. Foxp3 expression correlates with pleomorphic small and medium cell types and may be lost with large cell transformation. The evolution of the latter type can be associated with the gain of CD30 expression; such ATLL tumors might respond to anti-CD30 monoclonal antibody therapies.