In a cohort of 130 unselected chronic lymphocytic leukemia (CLL) patients, 73 cases had normal karyotypes, 57 cases had abnormal karyotypes, and 22/57 cases carried more than one abnormality. Trisomy 12 (+12) was the most common abnormality (26/130 cases; 20%), and 17/26 cases had isolated +12. Del(13q)/t13q/-13 was detected in 19/130 cases (14.6%), and 5/19 cases had isolated del(13)(q12q14). Deletion (11)(q23) and del(17p)/-17 were detected in 5/130 cases, respectively. CD38 expression was significantly more frequent in the +12/11q/17p versus the normal/del(13q) subgroups. A significant association was detected between +12 and FMC7 positivity. IGHV-unmutated cases were significantly more frequent in the +12/11q/17p subgroups. Patients with normal karyotype/del(13q) had a longer median time to progression versus the patients in the +12/11q/17p subgroups. According to multivariate analysis, only IGHV mutation status remained a statistically significant variable for progression-free survival (PFS). Furthermore, IGHV mutation status and clinical stage at diagnosis were the only significant prognostic factors for overall survival. Among Binet-A patients, significant parameters for shorter PFS were +12 or 11q/17p aberrations, CD38 expression, and IGHV unmutated status. In multivariate analysis, only CD38 expression and IGHV-unmutated status retained statistical significance for PFS. In conclusion, trisomy 12 in CLL is characterized by considerable heterogeneity and seems to be associated with disease progression.