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Lymphoproliferative disorders of natural killer (NK)-cell lineage are well documented in humans but have yet to be documented in non-human primates (NHPs). Here we describe a case of NK-cell lymphoproliferative disorder/leukemia in a 20-y-old captive female rhesus macaque ( Macaca mulatta ). The animal clinically had mild splenomegaly and marked lymphocytosis with small-to-medium lymphocytes in blood smears. By flow cytometry and cluster differentiation, the lymphocytes were CD3-negative, CD8-positive, CD4-negative, and CD20-negative for cell surface markers; immunohistochemistry revealed the presence of intracellular CD3 and granzyme B. This immunoprofile is consistent with a NK-cell phenotype. Histologically, these cells were predominantly intravascular within the splenic red pulp, liver sinusoids, and to a lesser degree bone marrow. Oncogenic viruses, such as Mason-Pfizer monkey viruses (MPMV; formerly, and commonly known as, simian retroviruses or SRV; Retroviridae , Betaretrovirus maspfimon ); simian immunodeficiency virus (SIV; Retroviridae , Lentivirus simimdef ), and primate T-lymphotropic virus 1 (PTLV1; commonly known as simian T-lymphotropic virus type 1, STLV1; Retroviridae , Deltaretrovirus priTlym1 ), were not detected in this animal by serology. Immunohistochemistry using EBNA2 antibody to detect rhesus and cynomolgus monkey lymphocryptovirus (McGHV4/RLV and McGHV10 respectively; Orthoherpesviridae , Lymphocryptovirus macacinegamma4 and Lymphocryptovirus macacinegamma13 , respectively) was negative. Together these findings are consistent with a diagnosis of naturally occurring NK-cell lymphoproliferative disorder. NK-cell lymphoproliferative disorder has not been reported previously in rhesus macaques, to our knowledge., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.