Context: Minimal residual disease (MRD) is a predictive marker for progression-free survival (PFS) in chronic leukocytic leukemia (CLL) following chemoimmunotherapy and fixed-duration treatment with venetoclax and anti-CD20 antibodies. This has not been explored for ibrutinib+venetoclax (Ibr+Ven), a fixed-duration treatment with mechanisms of action that synergistically eliminate CLL subpopulations in distinct tumor compartments. Objective: Investigate MRD outcomes at primary analysis of phase 3 GLOW study (NCT03462719). Design: Randomized, open-label, active-control study. Patients: Patients aged ≥65 years or 18–64 years with a CIRS score >6 or creatinine clearance <70 mL/min were randomized 1:1, stratified by IGHV mutational and del11q status, to Ibr+Ven (n=106) or chlorambucil+obinutuzumab (Clb+O) (n=105). Excluded: patients with del17p or known TP53 mutations. Interventions: Ibr+Ven (3 cycles of ibrutinib lead-in, then 12 cycles of Ibr+Ven) or 6 cycles of Clb+O. Main Outcome Measures: Primary endpoint: independent review committee–assessed PFS; secondary endpoint: rate of undetectable MRD (uMRD; <10^–4); exploratory endpoints: MRD analyses. MRD results are by next-generation sequencing, reported 3 months after end of treatment (EOT+3) unless otherwise noted. Results: Rates of uMRD<10^–4 were higher for Ibr+Ven versus Clb+O in bone marrow (BM) (51.9% vs. 17.1%; P<0.0001) and peripheral blood (PB) (54.7% vs. 39.0%; P=0.0259). For Ibr+Ven, BM uMRD was higher for uIGHV (58.2%) versus mutated IGHV (44.4%). With Ibr+Ven, 84.5% (49/58) of patients maintained PB uMRD from EOT+3 to EOT+12 versus 29.3% (12/41) with Clb+O. Rates of uMRD<10^–5 were higher for Ibr+Ven versus Clb+O in BM (40.6% vs. 7.6%), including patients with uIGHV (45.5% vs. 5.6%). uMRD<10^–5 in PB was largely sustained from EOT+3 to EOT+12 with Ibr+Ven (80.4% [37/46]) but not Clb+O (26.3% [5/19]). PFS rates for Ibr+Ven during the 12 months after EOT were >90% for patients with uMRD<10^–4 and patients with detectable MRD; however, Clb+O arm patients with detectable PB MRD relapsed more quickly than those with uMRD<10^–4. Conclusions: All-oral, once-daily, fixed-duration Ibr+Ven demonstrated superior uMRD responses that were deeper and better sustained post-treatment versus Clb+O in older adult or unfit patients with previously untreated CLL.