Fixed-duration venetoclax combinations have become a standard first-line treatment in chronic lymphocytic leukemia (CLL). The phase 3 CLL13/GAIA trial assesses three time-limited combinations: venetoclax-rituximab (RV), venetoclax-obinutuzumab (GV), and venetoclax-obinutuzumab-ibrutinib (GIV) compared to chemoimmunotherapy (CIT). Fit patients with CLL without TP53 aberrations were randomized between six cycles of CIT (fludarabine-cyclophosphamide-rituximab [FCR], bendamustine-rituximab [BR]) or 12 cycles of RV, GV or GIV (GIV: ibrutinib continuation until cycle 36 if measurable residual disease [MRD] at months 12/15). In total, 926 patients were randomized (GIV: 231, GV: 229, RV: 237, CIT: 229 [FCR: 150, BR: 79]). With a median observation time of 63.8 months, 5-year progression-free survival (PFS) rates were 81.3% (GIV), 69.8% (GV), 57.4% (RV), and 50.7% (CIT). PFS was superior for GV and GIV compared to CIT and RV (p<0.001 in each case). In addition, GIV showed longer PFS than GV (p=0.0046). Venetoclax-based retreatment after venetoclax-based first-line regimens was efficacious with 2-year treatment-free survival >80% from second-line treatment. No differences in overall survival were observed between treatment arms (5-year rates, GIV 94.3%; GV 93.6%; RV 94.7%; CIT 90.7%). Incidence rates of severe infections were highest with CIT while cardiac events were most frequent with GIV. Patients treated with GV or RV reported rapid and significantly greater quality of life (QoL) improvements compared to patients treated with CIT. In the GIV arm, clinically relevant QoL improvements occurred later (month 15, after the end of treatment in most patients) than with GV/RV, likely due to a higher treatment-related symptom burden. The trial is registered at clinicltrial.gov with the identifier, NCT02950051.