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Purpose: Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for patients with melanoma., Patients and Methods: Clinical data were extracted from the databases of 2 major melanoma centers in the United States and Australia for 1,918 patients with American Joint Committee on Cancer (AJCC) 8th edition stage III melanoma, diagnosed from 1998-2014, who had (negative) baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death, from stage III presentation and at benchmark time points 1, 2, and 5 years postdiagnosis., Results: At a median follow-up of 70.2 months, distant recurrence occurred in 711 patients (37.1%). The first site of distant metastasis was CNS only for 3.9% of patients, CNS and extracranial (EC) for 1.8%, and EC only for 31.4%. Overall, 16.7% of patients were diagnosed with CNS metastasis during follow-up. The cumulative incidence of CNS metastasis was 3.6% (95% CI, 2.9% to 4.6%) at 1 year, 9.6% (95% CI, 8.3% to 11.0%) at 2 years, and 15.8% (95% CI, 14.1% to 17.6%) at 5 years. The risk of CNS metastasis was significantly influenced by patient sex, age, AJCC stage, primary tumor site, and primary tumor mitotic rate in multivariable and conditional analyses. High primary tumor mitotic rate was significantly associated with increased risk of CNS metastasis at diagnosis and all subsequent time points examined., Conclusion: Similar rates of CNS metastasis were observed in 2 large, geographically distinct cohorts of patients with stage III melanoma. The results highlight the importance of primary tumor mitotic rate. Furthermore, they provide a framework for developing evidence-based surveillance strategies and evaluating the impact of contemporary adjuvant therapies on the risk of CNS metastasis development.