AbstractFluorescence in situ hybridization (FISH) to detect the recurrent cytogenetics abnormalities deletion 13q, trisomy 12, deletion 11q, and deletion 17p is important for prognostication in chronic lymphocytic leukemia (CLL). A subset of patients are negative for each of these abnormalities (normal 12/13/11/17 FISH), and outcomes are heterogenous within this group. To elucidate variables important for prognostication in this subgroup we conducted a retrospective analysis of 280 treatment‐naïve CLL patients with normal standard CLL FISH results. In a multivariable model, advanced Rai stage (p = 0.04, hazard ratio [HR] 1.24 (95% confidence interval [CI] 1.01–1.53)), unmutated immunoglobulin heavy chain gene (IGHV) (p < 0.0001, HR 5.59 (95% CI 3.63–8.62)) and IGH rearrangement by FISH (p = 0.02, HR 2.56 (95% CI 1.20–5.48)) were significantly associated with shorter time to first treatment. In a multivariable model for overall survival, increasing age at 5‐year increments (p < 0.0001, HR 1.55 (95% CI 1.25–1.93)), unmutated IGHV (p = 0.01, HR 5.28 (95% CI 1.52–18.35)) and gain of REL (p = 0.01, HR 4.08 (5% CI 1.45–11.49)) were significantly associated with shorter survival. Our study identifies variables important for refining prognosis for CLL patients with normal standard CLL FISH results.