Peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS), represents a heterogeneous group of nodal and extranodal lymphomas that express a variety of T-cell antigens indicative of mature T-cell lineage. Most cases of PTCL express CD4 and lack CD8 expression and have a T-helper immunophenotype. Although the immunophenotype of PTCL is usually stable over time, immunophenotypic switch or evolution from T-helper to T-suppressor or vice versa has been rarely reported. Herein, we report a patient who presented with nasal PTCL, NOS, that was CD8+ and negative for Epstein–Barr virus, with concurrent skin lesions that had a CD8+/TIA-1+ T-cell immunophenotype. Patient received multi-agent chemotherapy and matched unrelated donor stem cell transplant, and subsequently suffered a cutaneous relapse with a CD4+/TIA-1(−) immunophenotype. Molecular analysis of the neoplasm biopsied at presentation showed one monoclonal T-cell receptor gamma gene rearrangement, and a second oligoclonal peak. At the time of CD4-positive recurrence, the oligoclonal peak was rather prominent, suggesting that the emergence of this peak is related with the phenotypic evolution from CD8+ to CD4+ predominant. These results highlight the utility of sequential immunophenotypic and molecular analysis of PTCL cases at the time of relapse to better understand the mechanisms of disease.