Large granular lymphocyte leukemia (LGLL) is a rare and chronic lymphoproliferative disorder characterized by the clonal expansion of LGLs. LGLL patients can be asymptomatic or develop cytopenia, mostly neutropenia. Somatic STAT3 and STAT5b mutations have been recently reported in approximately 40% of patients. The aim of this study is to analyze clinical and biological features of a large cohort of LGLL patients to identify prognostic markers affecting patients' outcome. In 205 LGLL patients, neutropenia (ANC < 1500/mm3) was the main feature (38%), with severe neutropenia (ANC < 500/mm3) being present in 20.5% of patients. STAT3 mutations were detected in 28.3% patients and were associated with ANC < 500/mm3 (p < 0.0001), Hb < 90 g/L (p = 0.0079) and treatment requirement (p < 0.0001) while STAT5b mutations were found in 15/152 asymptomatic patients. By age-adjusted univariate analysis, ANC < 500/mm3 (p = 0.013), Hb < 90 g/L (p < 0.0001), treatment requirement (p = 0.001) and STAT3 mutated status (p = 0.011) were associated to reduced overall survival (OS). By multivariate analysis, STAT3 mutated status (p = 0.0089) and Hb < 90 g/L (p = 0.0011) were independently associated to reduced OS. In conclusion, we identified clinical and biological features associated to reduced OS in LGLL and we demonstrated the adverse impact of STAT3 mutations in patients' survival, suggesting that this biological feature should be regarded as a potential target of therapy.