Genomic aberrations are of predominant importance to the biology and clinical outcome of patients with chronic lymphocytic leukemia (CLL), and FISH-based genomic risk classifications are routinely used in clinical decision making in CLL. One of the known limitations of CLL FISH is the inability to comprehensively interrogate the CLL genome for genomic changes. In an effort at overcoming the existing limitations in CLL genome analysis, we have analyzed high-purity DNA isolated from FACS-sorted CD19(+) cells and paired CD3(+) or buccal cells from 255 patients with CLL for acquired genomic copy number aberrations (aCNAs) with the use of ultra-high-density Affymetrix SNP 6.0 arrays. Overall, ≥ 2 subchromosomal aCNAs were found in 39% (100 of 255) of all cases analyzed, whereas ≥ 3 subchromosomal aCNAs were detected in 20% (50 of 255) of cases. Subsequently, we have correlated genomic lesion loads (genomic complexity) with the clinical outcome measures time to first therapy and overall survival. With the use of multivariate analyses incorporating the most important prognostic factors in CLL together with SNP 6.0 array-based genomic lesion loads at various thresholds, we identify elevated CLL genomic complexity as an independent and powerful marker for the identification of patients with aggressive CLL and short survival.