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One of the main issues in the treatment of patients with chronic lymphocytic leukemia (CLL) deals with the choice between continuous or fixed-duration therapy. Continuous ibrutinib (IB), the first-in-class BTK inhibitor, and obinutuzumab-chlorambucil (G-CHL) are commonly used therapies for elderly and/or comorbid patients. No head-to-head comparison has been carried out. Within the Italian campus CLL network, we performed a retrospective study on CLL patients without TP53 disruption treated with IB or G-CHL as first-line therapy. Patients in the G-CHL arm had a higher CIRS score and the worst renal function. The overall response rates between the G-CHL and IB arms were similar, but more complete remissions (CRs) were achieved with G-CHL ( p = 0.0029). After a median follow-up of 30 months, the progression-free survival (PFS, p = 0.0061) and time to next treatment (TTNT, p = 0.0043), but not overall survival (OS, p = 0.6642), were better with IB than with G-CHL. Similar results were found after propensity score matching and multivariate analysis. While PFS and TTNT were longer with IB than with G-CHL in IGHV unmutated patients ( p = 0.0190 and 0.0137), they were superimposable for IGHV mutated patients ( p = 0.1900 and 0.1380). In the G-CHL arm, the depth of response (79% vs . 68% vs . 38% for CR, PR and SD/PD; p < 0.0001) and measurable residual disease (MRD) influenced PFS (78% vs . 53% for undetectable MRD vs . detectable MRD, p = 0.0203). Hematological toxicities were common in the G-CHL arm, while IB was associated with higher costs. Although continuous IB provides better disease control in CLL, IGHV mutated patients and those achieving an undetectable MRD show a marked clinical and economic benefit from a fixed-duration obinutuzumab-based treatment., Competing Interests: AV received honoraria from Janssen, Abbvie, CSL Behring, and Italfarmaco. LT received research funding from Gilead, Roche, Janssen, and Takeda, and is on the advisory board for Roche, Takeda, Abbvie, and AstraZeneca. GR received research funding from Gilead. FM is on the advisory board for Janssen, Takeda, and Abbvie. ACu is on the advisory board and speaker bureau for Roche, Abbvie, Gilead, and Janssen. RF is on the advisory board or speaker bureau for Incyte, Amgen, AstraZeneca, Janssen, Gilead, and Novartis. LL received honoraria from Abbvie, Janssen, Astra Zeneca, and Beigene. FQ plays an advisor role for AstraZeneca and Janssen, is a speaker for Janssen, and is a consultant for Sandoz. LS received honoraria from AbbVie, AstraZeneca, and Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Visentin, Mauro, Catania, Fresa, Vitale, Sanna, Mattiello, Cibien, Sportoletti, Gentile, Rigolin, Quaglia, Murru, Gozzetti, Molica, Marchetti, Pravato, Angotzi, Cellini, Scarfò, Reda, Coscia, Laurenti, Ghia, Foà, Cuneo and Trentin.)