In 2018, members of our team published an interesting case of a patient with newly diagnosed aggressive relapsing-remitting multiple sclerosis (RRMS) who experienced significant improvement in both neurological symptoms and fatigue after starting Combivir (zidovudine/lamivudine) in the absence of disease-modifying therapies (DMTs). (Drosu et al., 2018) Since this patient was negative for HIV, it prompted an intriguing hypothesis that the effect of treatment may be attributable to the known direct activity of zidovudine as an antiviral against EBV and, therefore, the larger question of whether MS could ultimately be treatable with drugs targeting EBV lytic reactivation. Given prior negative trials with acyclovir, (Lycke, 2017) we suggested that it might be prudent to avoid classical anti-herpesvirus drugs and instead use compounds that bypass the rate-limiting step of viral kinase-dependent drug metabolism, like those used for the treatment of HIV. (Drosu et al., 2018) Since circumstantial epidemiological evidence of a lower incidence of MS in patients with HIV supported the possible existence of other HIV drugs with anti-EBV effects, (Gold et al., 2015; Nexø et al., 2013) our team then screened these compounds for activity against EBV in vitro, which led to the identification of tenofovir prodrugs as compounds with superior anti-EBV activity. (Drosu et al., 2020) Here, we provide an update on that case and discuss implications for future clinical trials.