INTRODUCTION: After primary infection, human herpesviruses establish latency and persist lifelong. Periodic virus reactivation can lead to serious inflammatory complications. Recent research suggests that herpesvirus reactivation may also be linked to acute stroke. An improved understanding of this relationship is vital to inform public health prevention strategies. We will review the evidence regarding the role of human herpesviruses in triggering stroke. METHODS AND ANALYSIS: A systematic literature review of published and grey literature studies with a human herpesvirus (infection or reactivation) as an exposure and stroke as an outcome will be carried out. Randomised controlled trials, cohort, case-control, case crossover and self-controlled case series designs will be eligible; no restrictions will be placed on publication status, language and geographical or healthcare setting. The Cochrane Central Register of Controlled Trials, Embase, Global Health, Medline, Scopus and Web of Science will be searched from dates of inception to January 2017. A prespecified search strategy of medical subject headings and free text terms (in the title and abstract) for human herpesviruses AND stroke will be used. Two reviewers will independently screen titles and abstracts for eligible studies, followed by full-text screening. The reviewers will then extract data from the eligible studies using standardised, pilot-tested tables and assess risk of bias in individual studies, in line with the Cochrane Collaboration approach. The data will be synthesised in a narrative format, and meta-analyses considered where there are sufficient data. Quality of evidence will be assessed in line with theGrading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. ETHICS AND DISSEMINATION: As this is a systematic review, ethical approval is not required. The results will be submitted for peer-review publication and presented at national conferences. A lay and short summary will be disseminated on appropriate webpages. PROSPERO REGISTRATION NUMBER: CRD42017054502.