• NK-cell neoplasms have higher CD94 expression than that in T cell neoplasms. • CD94 expression is positive in all HSTCL and 56 % of T-LGLL. • All T-PLL and 97 % of PTCL show no CD94 expression. • CD94 expression patterns and levels differ greatly in T and NK-cell neoplasms. Lymphomas and leukemias of T-cell and NK-cell lineages are highly heterogeneous disorders and lack effective therapeutic strategies. Targeted therapies including anti-CD94 agents are currently under clinical investigation, but studies of CD94 expression on mature T/NK-cell neoplasms are limited. In this study, we investigated the landscape of CD94 protein expression in 15 patients with reactive T/NK-cell proliferations and 124 patients with various T/NK cell neoplasms. CD94 expression was detected at a high level in reactive NK-cells, with a lower level of expression in a subset of reactive CD8 + T-cells; reactive CD4 + T-cells were negative for CD94 expression. All NK-cell neoplasms surveyed had high-level CD94 expression, which was significantly higher than that in T cell neoplasms ( p = 0.0174). In neoplastic T-cell proliferations, CD94 expression was positive in all 10 hepatosplenic T-cell lymphoma cases tested, with a high mean fluorescence intensity. Fifty-six percent of T-cell large granular lymphocytic leukemia cases were positive for CD94 expression in a subset of neoplastic cells. All T-cell prolymphocytic leukemia and 97 % of peripheral T-cell lymphoma cases showed no CD94 expression. Our findings demonstrate a broad range of CD94 expression among T/NK-cell neoplasms, in some at levels that suggest therapeutic vulnerability to CD94-targeted therapies.