Chronic lymphocytic leukemia (CLL) patients with differentialsomatic hypermutation status of the immunoglobulin heavy vari-able genes, namely mutated or unmutated, display fundamentalclinico-biological differences. Considering this, we assessed prognosisseparately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015patients, hypothesizing that the relative significance of relevant indica-tors may differ between these two categories. Within Binet A M-CLLpatients, besides TP53abnormalities, trisomy 12 and stereotyped subset#2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at five and ten years afterdiagnosis of 40% and 55%, respectively; the remaining cases exhibited5-year and 10-year treatment probability of 12% and 25%, respectively.Within Binet A U-CLL patients, besides TP53abnormalities, del(11q)and/or SF3B1mutations were associated with the shortest time-to-first-treatment (5- and 10-year treatment probability: 78% and 98%, respec-tively); in the remaining cases, males had a significantly worse prognosisthan females. In conclusion, the relative weight of indicators that canaccurately risk stratify early-stage CLL patients differs depending on thesomatic hypermutation status of the immunoglobulin heavy variablegenes of each patient. This finding highlights the fact that compartmen-talized approaches based on immunogenetic features are necessary torefine and tailor prognostication in CLL.