Hairy cell leukemia (cHCL) patients have, in most cases, a specific clinical and biological presentation with splenomegaly, anemia, leukopenia, neutropenia, monocytopenia and/or thrombocytopenia, identification of hairy cells that express CD103, CD123, CD25, CD11c and identification of the V600E mutation in the B-Raf proto-oncogene () in 90% of cases. Monocytopenia is absent in vHCL and SDRPL patients and the abnormal cells do not express CD25 or CD123 and do not present the mutation. Ten percent of cHCL patients are BRAF and the distinction between cHCL and HCL-like disorders including the variant form of HCL (vHCL) and splenic diffuse red pulp lymphoma (SDRPL) can be challenging. We performed deep sequencing in a large cohort of 84 cHCL and 16 HCL-like disorders to improve insights into the pathogenesis of the diseases. mutations were detected in 76/82 patients of cHCL (93%) and additional mutations were identified in Krüppel-like Factor 2 () in 19 patients (23%) or in 6 patients (7.5%). Some genetic alterations were localized on the cytidine deaminase (AID) consensus motif, suggesting AID-induced mutations. When analyzing sequential samples, a clonal evolution was identified in half of the cHCL patients (6/12 pts). Among the 16 patients with HCL-like disorders, we observed an enrichment of mutations in vHCL/SDRPL (3/5 pts) and genes involved in the epigenetic regulation () (3/5 pts). Furthermore, mutations were associated with a bad prognosis and a shorter time to next treatment (TTNT) and progression-free survival (PFS), independently of the HCL classification.