<b><i>Introduction:</i></b> Chronic fatigue syndrome (CFS) is a neurological disease that is accompanied by excessive fatigue or tiredness. There are several reports confirming the association between human herpesvirus 6 (HHV-6) infection and CFS illness. This systematic review and meta-analysis was performed to integrate the information of published studies with regard to this association until May 2021. <b><i>Methods:</i></b> The literature search was based on keywords including “chronic fatigue syndrome and HHV 6,” “chronic fatigue syndrome and HHV-6,” “chronic fatigue syndrome and HHV6,” “chronic fatigue syndrome and Herpes virus 6,” and “chronic fatigue syndrome and Herpesvirus6” in MEDLINE (PubMed), Web of Science, and EMBASE. <b><i>Results:</i></b> The literature search identified 17 studies to be included in the systematic review and 11 studies in meta-analysis. The symmetry funnel plot and Egger’s test (<i>p</i> value = 0.2) identified no publication bias among studies. Moreover, the low level of <i>I</i><sup>2</sup> revealed homogeneity across studies. <b><i>Discussion:</i></b> In conclusion, the association between the HHV-6 infection and CFS incidence was substantiated. However, the results of this study also suggest that further comprehensive studies are needed to solidify the association between HHV-6 and CFS. Future studies should consider additional factors that may have affected the significance of such a correlation.
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