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Background: Sparganosis is a parasitic infection caused by the plerocercoid larvae of Spirometra mansoni in East and Southeast Asia. The plerocercoid larvae sometimes invade the encephalon, resulting in severe cerebral sparganosis. Surgical removal of the larvae is considered a standard therapy for cerebral sparganosis. In contrast, the efficacy and safety of long-term, high-dose praziquantel treatment for cerebral sparganosis have not been explored., Methodology/principal Findings: In this multicenter retrospective study, we assessed the records of 96 patients with cerebral sparganosis who consulted at three medical centers from 2013 to 2017. Forty-two patients underwent surgical lesion removal, and the other 54 patients received long-term, high-dose praziquantel (50 mg/kg/day for 10 days, repeated at monthly intervals). The primary outcome was the complete disappearance of active lesions on cerebral magnetic resonance imaging. The secondary outcomes included the modified Rankin scale score at 90 days, incidence of seizure, eosinophil count, and serological Spirometra. mansoni antibody titer. The efficacy of praziquantel treatment was similar to that of surgical lesion removal for cerebral sparganosis with respect to both the primary outcome and secondary outcomes. Although binary logistic regression models also supported the primary outcome after adjustment for age, sex, lesion location, and loss to follow-up, some unavoidable confounders might have biased the statistical power. No significant clinical complications or laboratory side effects occurred in the praziquantel group with the exception of a relatively benign allergic reaction., Conclusions/significance: In this small-sample, nonrandomized, retrospective exploratory study, some patients with cerebral sparganosis were responsive to long-term, high-dose praziquantel with an efficacy similar to that of surgical lesion removal. These findings increase the treatment flexibility for this serious infection., Competing Interests: The authors have declared that no competing interests exist.