Central nervous system (CNS) involvement in Burkitt lymphoma poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We describe the prognostic significance of CNS involvement and the incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathological data from adults with Burkitt lymphoma diagnosed between 2009 and 2018 in 30 institutions in the USA. We examined associations between baseline CNS involvement, patients' characteristics, complete response rates, and survival. We also examined risk factors for CNS recurrence. Of 641 patients (aged 18 to 88 years), 120 (19%) had CNS involvement. CNS involvement was independently associated with human immunodeficiency virus infection, poor performance status, involvement of ≥2 extranodal sites, and bone marrow involvement. Selection of the first-line treatment regimen was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of complete response (59% vs. 77% for patients with and without CNS involvement, respectively; P<0.001), worse 3-year progression-free survival (adjusted hazard ratio [aHR]=1.53, 95% confidence interval [95% CI]: 1.14-2.06; P=0.004) and overall survival (aHR=1.62, 95% CI: 1.18-2.22; P=0.003). The 3-year cumulative incidence of CNS recurrence was 6% (95% CI: 4-8%) and was significantly lower among patients receiving other regimens (CODOX-M/IVAC, 4%, or hyperCVAD/MA, 3%) compared with DA-EPOCH-R (13%; adjusted sub-distribution HR=4.38, 95% CI:, 2.16-8.87; P<0.001). Baseline CNS involvement in Burkitt lymphoma is relatively common and portends inferior prognosis independently of the first-line treatment regimen selected. In real-world practice, regimens including intravenous systemic agents with pronounced CNS penetrance were associated with a lower risk of CNS recurrence. This finding may be influenced by observed suboptimal adherence to the strict CNS staging and intrathecal therapy procedures incorporated in the DA-EPOCH-R regimen.