This study aimed to determine whether the phenotypic characteristics of the two subtypes of CD56+ and CD56- lymphoma have relevance for their clinical behavior and prognosis. The immunophenotypes of all patients were confirmed using standard criteria for CD20, CD3ε, CD56, cytotoxic molecules (T-cell intracellular antigen-1 [TIA-1] and granzyme B), and Ki-67, and in situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER). CD56 was expressed in 90 of 118 (76.3%) patients. The majority (83.3%) of patients with nasal natural killer/T-cell lymphoma (NKTCL) presented with CD56+ lymphoma, whereas patients with NKTCL of the extranasal upper aerodigestive tract were more likely to have CD56- lymphoma (53.6%, p < 0.000). A lower percentage of expression of granzyme B and Ki-67 (>50%) was found in patients with CD56- lymphoma compared with those with CD56+ lymphoma (p <0.05). The clinical characteristics and prognosis were comparable between patients with CD56+ and CD56- lymphomas. The corresponding overall survival and progression-free survival rates were 74.1% and 56.7%, respectively, for patients with CD56+ lymphoma compared with 81.6% and 60.5% for those with CD56- lymphoma (p > 0.05). There was no clinical or prognostic significance in determining the two subtypes of CD56+ and CD56- NKTCL based on their immunophenotypic profiles, which has clinical implications for pathological diagnosis and insight into disease behavior.