Background: In the GLOW study, fixed-duration ibrutinib–venetoclax showed superior progression-free survival versus chlorambucil–obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia who were older or had comorbidities, or both, at a median follow up of 27·7 months. In this Article, we report updated outcomes from GLOW after a 46-month median follow-up. Methods: GLOW was a randomised, multicentre, phase 3 study done at 67 hospital centres across 14 countries. Patients aged 65 years and older or 18–64 years with previously untreated chronic lymphocytic leukaemia and a cumulative illness rating scale score of more than 6 or creatinine clearance less than 70 mL/min, or both, and an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) via an interactive web system with permuted blocks (block size of four) and stratified by IGHV mutational status and the presence of del11q aberration to the ibrutinib–venetoclax group (three cycles of ibrutinib lead-in [420 mg/day, orally], followed by 12 cycles of ibrutinib plus venetoclax [400 mg/day, orally, including a 5-week dose ramp-up]) or the chlorambucil–obinutuzumab group (six cycles of chlorambucil [0·5 mg/kg, orally, on days 1 and 15 of each cycle], and obinutuzumab [1000 mg, intravenously, on days 1 (or 100 mg on day 1 and 900 mg on day 2), 8, and 15 of cycle 1 and day 1 of cycles 2–6]). The primary endpoint was progression-free survival in the intention-to-treat population, assessed by an independent review committee. The safety population included all randomised patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov (NCT03462719) and the EU Clinical Trials Register (EudraCT 2017-004699-77). Findings: Between May 4, 2018, and April 5, 2019, 211 patients (122 [58%] were male and 89 [42%] were female) were randomly assigned to receive ibrutinib–venetoclax (n=106) or chlorambucil–obinutuzumab (n=105). At a median of 46 months (IQR 43–47) of follow-up, progression-free survival remained superior for the ibrutinib–venetoclax group (hazard ratio 0·214 [95% CI 0·138–0·334]; p<0·0001); 42-month progression-free survival rates were 74·6% (95% CI 65·0–82·0) for ibrutinib–venetoclax and 24·8% (16·5–34·1) for chlorambucil–obinutuzumab. Following the primary analysis, one patient in the chlorambucil–obinutuzumab group had a serious adverse event of myelodysplastic syndrome. Treatment-related deaths were reported in one patient receiving ibrutinib–venetoclax (cardiac failure, pneumonia, and sinus node dysfunction) and in one patient receiving chlorambucil–obinutuzumab (pneumonia). There were 15 deaths in the ibrutinib–venetoclax group (of which three were due to post-treatment infections) and 30 deaths in the chlorambucil–obinutuzumab group (of which 10 were due to post-treatment infections). Interpretation: After 4 years of follow-up, ibrutinib–venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukaemia, supporting its use as a first-line option. Funding: Janssen Research & Development and Pharmacyclics.