PURPOSE: CNS involvement in North American adult T-cell leukemia/lymphoma (NA-ATLL) remains poorly understood. This study examined the CNS involvement in patients with ATLL treated at a tertiary hospital in New York City. METHODS: CNS involvement was defined by positive cerebrospinal fluid (CSF) cytology, flow cytometry, positive CNS imaging, or neurological examination findings. RESULTS: Among 94 patients with NA-ATLL, 21 (22.3%) had CNS involvement. CSF was involved in 13 patients at diagnosis and five at relapse. Magnetic resonance imaging detected brain and spinal involvement in 24% and 14% of the patients, respectively. Results of neurological examinations were abnormal in 33% and 14% of the patients at diagnosis and relapse, respectively. The mutation was found in two patients with extensive, treatment-refractory CNS disease, with a median overall survival (OS) of 2 months. Other mutations, including and , were noted in two patients. The median OS was 8.5 months, and the median relapse-free survival (RFS) was 6.5 months in our series. In most cases (5/21), the lymphomatous phenotype appeared to have a direct mass-like extension, whereas in patients with predominant blood involvement tended to spread to the CSF by traversing the blood-brain barrier. CONCLUSION: In this report, we describe the patterns of CNS involvement in ATLL and their association with mutations. We also describe two rapidly fatal cases with the mutation, which may represent a novel therapeutic target for T-cell lymphomas.