OBJECTIVES:  Ibrutinib has demonstrated superiority in terms of efficacy and tolerability to chlorambucil (Chl) for TN-CLL patients who are elderly or unfit (RESONATE-2). Within this trial there is a subgroup of less fragile patients, defined as those having a Cumulative Illness Rating Scale (CIRS) score ≤6 or Creatinine clearance (ClCr)≥60 ml/min that could be potential candidates for bendamustine-rituximab (BR) therapy. As no head-to-head comparison exists for this relatively fit subgroup, an NMA was conducted to compare the efficacy of ibrutinib vs. BR in patients suitable for chemoimmunotherapy. METHODS:  Out of sixteen randomized controlled trials (RCTs) in TN-CLL patients identified in a systematic literature review, four RCTs were conducted in patients/subgroups of patients who were relatively younger or more fit (CLL8, Hallek 2010; CLL10, Eichorst 2016; LRF CLL4, Catowsky 2007; RESONATE-2, the less fragile subgroup, data at a median follow-up of 28.6 months). They are connected in a network of evidence that could inform the indirect comparison of interest. A Bayesian NMA was conducted to compare hazard ratios (HR) of overall survival (OS) and progression-free survival (PFS) of ibrutinib vs. BR, FC, FCR and Chl. A fixed effect model was used due to the limited size and structure of the network. RESULTS:  Ibrutinib had favorable HRs and the highest pairwise probability of being the best treatment (P) in terms of PFS and OS versus BR (HR=0.36/0.55, P=100%/87%), FC (HR=0.33/0.36, P=100%/99%), FCR (HR=0.59/0.53, P=95%/92%) and Chl (HR=0.14/0.40, P=100%/99%). Ibrutinib had the highest probability of being the best treatment in the network in terms of PFS (99%) and OS (94%). CONCLUSIONS:  This analysis suggests that ibrutinib is a more effective treatment compared to BR in terms of survival outcomes PFS and OS in TN-CLL patients who are relatively younger or more fit, defined as having a CIRS≤6 or ClCr≥60 ml/min.