Large granular lymphocyte leukemia (LGL) is often associated with immune cytopenias and can co-occur in the context of aplastic anemia (AA) and myelodysplastic syndromes (MDS). We took advantage of the recent description of STAT3 mutations in LGL clonal expansions to test, using sensitive methods, for the presence of these mutations in a large cohort of 367 MDS and 140 AA cases. STAT3 clones can be found not only in known LGL concomitant cases, but in a small proportion of unsuspected ones (7% AA and 2.5% MDS). In STAT3 mutated AA patients, an interesting trend toward better responses of immunosuppressive therapy and an association with the presence of HLADR15 were found. MDSs harboring a STAT3 mutant clone showed lower degree of BM cellularity and a higher frequency of developing chromosome 7 abnormalities. STAT3-mutant LGL clones may facilitate a persistently-dysregulated autoimmune activation, responsible for the primary induction of bone marrow failure in a subset of AA and MDS patients.