and ( ) mutations are the most common mutations in T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorders of NK cells (CLPD-NK), but their clinical impact remains unknown. We investigated the frequency and type of mutations in FACS-sorted populations of expanded T/NK-LGL from 100 (82 clonal; 6 oligoclonal; 12 polyclonal) patients, and its relationship with disease features. Seventeen non-LGL T-CLPD patients and 628 age-matched healthy donors were analyzed as controls. ( = 30) and ( = 1) mutations were detected in 28/82 clonal T/NK-LGLL patients (34%), while absent (0/18, 0%) among oligoclonal/polyclonal LGL-lymphocytosis. Mutations were found across all diagnostic subgroups: TCD8 -LGLL, 36%; CLPD-NK, 38%; TCD4 -LGLL, 7%; Tαβ DP-LGLL, 100%; Tαβ DN-LGLL, 50%; Tγδ -LGLL, 44%. -mutated T-LGLL/CLPD-NK showed overall reduced ( < 0.05) blood counts of most normal leukocyte subsets, with a higher rate (vs. nonmutated LGLL) of neutropenia ( = 0.04), severe neutropenia ( = 0.02), and cases requiring treatment ( = 0.0001), together with a shorter time-to-therapy ( = 0.0001), particularly in non-Y640F mutated patients. These findings confirm and extend on previous observations about the high prevalence of mutations across different subtypes of LGLL, and its association with a more marked decrease of all major blood-cell subsets and a shortened time-to-therapy.