BACKGROUND: Chronic migraine (CM) is a debilitating neurological disorder that imposes substantial burdens on individuals and society, including diminished quality of life and increased healthcare utilization. While the efficacy of botulinum neurotoxin type A (BoNT-A) has been demonstrated in controlled trials, this longitudinal, real-world study offers unprecedented evidence of its long-term benefits, with patients followed for a median of 15 months (interquartile range: 6-36 months) and up to 11 years. METHODS: This retrospective analysis included 579 patients diagnosed with CM who were newly treated with BoNT-A, according to the PREEMPT protocol, receiving injections every 12 weeks at doses of 155-195 units across 31-39 sites. Outcomes were assessed through changes in monthly headache days, frequency, symptomatic medication use, and migraine-related disability using Migraine Disability Assessment (MIDAS) scores up to 60 months from recruitment. Safety was evaluated by recording treatment-emergent adverse events (TEAEs), with a focus on long-term tolerability and subgroup variability. RESULTS: Patients showed sustained improvements, with the mean number of monthly headache days decreasing from 22.7 to 5.5, and symptomatic medication use dropping from 33.4 to 3.7 mean doses at 60 months. Additionally, over 60% of patients improved from severe (MIDAS Grade IV) to minimal disability (MIDAS Grade I). Subgroup analysis revealed variability in response rates, emphasizing the need for personalized approaches. TEAEs were predominantly mild, with no new adverse events reported after 36 months, supporting the long-term safety of BoNT-A in real-world settings. CONCLUSIONS: This real-world study provides significant evidence for the long-term efficacy, safety, and tolerability of BoNT-A in the preventive treatment of CM. The findings highlight the importance of real-world data to account for patient variability and tailoring treatment strategies.