Status epilepticus (SE) is the second most critical neurological illness after cerebrovascular disease. Phenytoin has traditionally been considered the second-line drug of first choice after failure of first line treatment using benzodiazepines. In recent years, levetiracetam has been proposed as a potential substitute for phenytoin. To comprehensively evaluate the efficacy and safety of levetiracetam and phenytoin in the treatment of patients with established SE, we integrated the data from 11 eligible studies and conducted a systematic review and meta-analysis. The PubMed, Web of Science, Cochrane Library, and Embase databases were searched to identify eligible articles reporting outcomes including clinical seizure cessation within 60 min, clinical recurrence rate within 24 h, good final outcome at discharge, and adverse events (AEs) of treatment with levetiracetam and phenytoin. Our study included a total of 11 trials including a total of 1933 patients. The outcomes showed that the pooled Risk Raito (RR) of clinical seizure cessation within 60 min was 1.08 (95% CI = 1.02 & ndash;1.14, P = 0.01). The pooled RR of clinical recurrence rate within 24 h was 1.03 (95% CI = 0.66 & ndash;1.59, P = 0.91). The pooled RR of AEs was 0.83 (95% CI = 0.57 & ndash;1.21, P = 0.34). The pooled RRs of life-threatening hypotension and acute respiratory depression were 0.29 (95% CI = 0.10 & ndash;0.81, P = 0.02) and 0.63 (95% CI = 0.40 & ndash;0.98, P = 0.04), respectively. Levetiracetam might be more effective than phenytoin for the treatment of established SE and is associated with a lower incidence of more serious AEs. Levetiracetam can be used as an alternative to phenytoin for the treatment of benzodiazepine-refractory SE. (c) 2021 Published by Elsevier Ltd.