Complex karyotypes have been associated with inferior outcomes in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT) while their prognostic impact in the context of venetoclax-based treatments is still debated. In this prospective analysis on karyotype complexity in CLL, we evaluated the impact of complex (≥3 chromosomal aberrations [CA], CKT) and highly complex karyotypes (≥5 CA, hCKT) as well as specific aberrations in previously untreated patients without TP53 aberrations undergoing either CIT or time-limited venetoclax-based therapies in the phase 3 GAIA/CLL13 trial. Karyotype analyses were available for 895 of 926 (96.7%) patients of whom 153 (17%) had a CKT and 43 (5%) hCKT. In the CIT arm, CKT was associated with shorter PFS (HR 2.58, 95%CI 1.54-4.32, p<0.001) and OS (HR 3.25, 95%CI 1.03-10.26, p=0.044). In the pooled venetoclax arms a multivariable analysis identified hCKT (HR 1.96, 95%CI 1.03-3.72, p=0.041) but not CKT as independent adverse prognosticators for PFS. The presence of translocations (unbalanced and/or balanced) was also independently associated with shorter PFS in the venetoclax arms. CIT led to the acquisition of additional CA (mean CA: 2.0 to 3.4, baseline to CLL progression) while karyotype complexity remained stable after venetoclax-based treatments (2.0, both time points). This analysis establishes highly complex karyotypes and translocations as adverse prognostic factors in the context of venetoclax-based combination treatments. The findings of this study support the incorporation of karyotyping into the standard diagnostic work-up of CLL as it identifies patients at high risk for poor treatment outcomes and thereby improves prognostication.