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Abstract Background: The treatment landscape of chronic lymphocytic leukemia (CLL) has shifted with the adoption of targeted therapies administered either as fixed-duration ( venetoclax-obinutuzumab [VenO]) or continuous regimens ( Bruton tyrosine kinase inhibitors [BTKis]). While clinical trials have established efficacy for both approaches, real-world comparative evidence - particularly regarding time to next treatment, treatment-free intervals, and patient-centered outcomes still remains limited. We aimed to evaluate and compare the real-world effectiveness and patient-centered outcomes of fixed-duration versus continuous first-line CLL therapies. Methods: A comprehensive search was performed across PubMed, Embase, Web of Science, and Cochrane for studies published between January 2010 and June 2025. Eligible studies included real-world observational cohorts comparing fixed-duration versus continuous first-line therapies in adults with chronic lymphocytic leukemia. Primary outcomes included time to next treatment (TTNT), progression-free survival (PFS), overall survival (OS), and adverse outcomes. Data extraction and risk-of-bias assessments were performed independently by two reviewers using a standardized format and appropriate quality assessment tools. Results: A total of four real-world observational studies involving 8,783 patients with CLL were included.The first-line treatment patterns predominantly included BTKis (40–60%) and VenO(12–16%). At 12 months, time to next treatment or death significantly favored VenO over BTKis (87.1% vs. 75.3%; p < 0.01). Median duration of therapy (DoT) for VenO was approximately 12.3 months, consistent with its fixed-duration schedule, whereas BTKi regimens, administered continuously, had DoTs ranging from 5.9 to 11.5 months. Among patients who discontinued therapy, those receiving VenO had a markedly longer median time off treatment (11.3 vs. 4.3 months). Two-year follow-up showed 86.3% of VenO patients remained treatment-free or alive, comparable or superior to BTKis. Treatment persistence and sequencing patterns were also favorable for VenO, suggesting durability despite fixed duration. In contrast, anti-CD20 monotherapy and chemoimmunotherapy were associated with shorter TTNT-D and inferior outcomes, reinforcing the evolving standard of care favoring novel targeted agents. Conclusions: Venetoclax-based fixed-duration regimens demonstrate strong real-world effectiveness with the added benefit of extended treatment-free intervals and favorable time-to-next-treatment outcomes, offering a patient-centered advantage over continuous BTKi therapy. These findings support the role of time-limited therapy in frontline CLL treatment algorithms and shared decision-making.