Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy but less well studied with novel compounds. We assessed IGHV mutation status, common genomic aberrations and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942) comparing obinutuzumab+chlorambucil (GClb) vs. obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +(12) 18% and del(13q) 35%, while IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%) and TP53 (10%). While the overall response rate (ORR) for GClb was lower in patients with del(17p), del(11q), mutated TP53, ATM and BIRC3, none of these parameters reduced complete remission (CR) and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with impact on PFS for both treatment arms, GClb (HR 4.6, p<0.01, HR 2.7, p<0.01) and VenG (HR 4.4, p<0.01, HR 3.1 p<0.01). No other factors affected outcome with VenG, while for GClb del(11q), BIRC3, NOTCH1 and unmutated IGHV associated with shorter PFS. Multivariable analysis identified del(17p), del(11q), unmutated IGHV and mutated TP53, BIRC3 and SF3B1 as independent prognostic factors for PFS with GClb, while for VenG only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. Especially patients with adverse genetic markers had the strongest benefit from VenG, particularly subjects with unmutated IGHV, which was identified as a predictive factor in a multivariable treatment-interaction analysis.