OBJECTIVES:  As there are no head-to-head trials of ibrutinib versus obinutuzumab plus chlorambucil (OBI+CHLOR) in patients with previously untreated CLL, a MAIC was performed to assess their relative effects on progression-free survival (PFS) and overall survival (OS) while adjusting for potential treatment effect modifiers. METHODS:  Individual patient data from RESONATE-2 (ibrutinib versus CHLOR) and aggregate data from CLL11 (OBI+CHLOR versus CHLOR) were available. As per the MAIC technique, patients from RESONATE-2 not meeting the CLL11 inclusion criteria were excluded. The remaining RESONATE-2 patients were reweighted to match all relevant baseline characteristics reported for CLL11 (CIRS score, age, Binet stage, β-microglobulin, del11q, ECOG status, creatinine clearance, sex and unmutated IGHV). Hazard ratios (ibrutinib vs CHLOR) for investigator assessed (INV) PFS, independent review committee (IRC) assessed PFS and OS were recalculated for the weighted population and subsequently used in a Bayesian Network Meta-Analysis to compare with OBI+CHLOR. The results were compared with those of a traditional indirect comparison (IC). RESULTS:  The traditional IC HRs [95% credible interval (CrI), probability HR<1 (p(HR<1))] of ibrutinib versus OBI+CHLOR for PFS INV, PFS IRC and OS were 0.48 [CrI=0.22–1.02, p(HR<1)=97%], 0.85 [CrI=0.44–1.63, p(HR<1)=69%] and 0.40 [CrI=0.10–1.54, p(HR<1)=91%], respectively. Of the total trial population of 136/133 (ibrutinib/CHLOR) participants in RESONATE-2, 95 and 96, respectively satisfied the CLL11 inclusion criteria. After matching, all available baseline characteristics were balanced across trial populations. MAIC adjusted HRs were 0.12 [CrI=0.02–0.97, p(HR<1)=98%] (PFS INV), 0.24 [CrI=0.04–1.35, p(HR<1)=95%] (PFS IRC) and 0.21 [CrI=<0.01–8.89, p(HR<1)=79%] (OS). CONCLUSIONS:  This analysis shows that while results of a traditional IC are in favour of ibrutinib, they still represent an underestimation of the true treatment benefit of ibrutinib on PFS and OS; namely, a 95% probability for PFS by IRC and 79% for OS of ibrutinib being better than OBI+CHLOR.