Background: AlthoughCLL primarily affects older adults (median age 71 years), limited data exists about the outcomes of adults who are ≥80 years old because they are under-enrolled on clinical trials. Methods: The Mayo Clinic CLL Database was used to conduct a retrospective cohort study of adults ≥80 years at the time of frontline CLL treatment. Kaplan-Meier analysis was used to plot OS, and cumulative incidence was used to plot TTNT, accounting for competing risk of death. The Mayo Clinic IRB approved the study. Results: Our study included 216 patients with CLL who were age ≥80 years at the time of frontline CLL therapy between 1/1995 and 11/2022 (Table). The median time from CLL diagnosis to initiation of frontline therapy was 3.1 years. The median OS after start of frontline therapy was 3.9 years. The median OS was 3.3 years (95% CI 2.6–4.2) for patients who received alkylating agents (e.g., chlorambucil, n=96), 3.8 years (95% CI 2.8–not reached [NR]) for purine analogues (e.g., fludarabine, n=11), 3.9 years (95% CI 3.2–4.9) for anti-CD20 monoclonal antibody monotherapy (e.g., obinutuzumab, n=64), and not reached (95% CI 3.3-NR) for novel agents (n=43) (P=0.02). The types of novel agents included ibrutinib (n=19), acalabrutinib (n=16), venetoclax (n=7), and orelabrutinib (n=1). There was no difference in OS between 36 patients who received a BTKi compared to the 7 patients who received venetoclax-based therapy. At a median follow-up time of 6.7 years from the first visit, 143 patients died from the following: progressive CLL (n=63), infections (n=12), other cancer (n=11), non-CLL reasons (n=21). Cause of death was unavailable for 36 patients. On multivariable analyses, older age (i.e., any 5-year increase in age) was associated with a 50% increased risk of death (HR 1.5, 95% CI 1.2-1.9, p=0.001), and treatment with non-novel agents was associated with 3.2 times increased risk of death (HR 3.2, 95% CI 1.2-8.9, p=0.02). Of the 216 patients, 76 patients required second-line therapy; the median TTNT was 4.2 years (95% CI 2.9-NE). The most used second-line agents were monoclonal antibodies alone (20/76, 26%) and single-agent alkylators (18/76, 24%). Conclusions: When compared to all other CLL treatments, novel agents such as BTKi and venetoclax-based treatments are associated with significantly improved OS in patients with CLL ≥80 years old when used in the frontline setting.