<h3>Objective(s)</h3> Infections of the central nervous system (CNS) can create a range of cognitive deficits in the domains of memory, attention, and executive functioning. The objective of this study was to summarize scientific evidence on the effectiveness of pharmacological therapy aiming to improve cognition in patients with primary CNS infections. <h3>Data Sources</h3> We searched for longitudinal studies published from inception to November 2019 within Medline, Embase, and CENTRAL databases. <h3>Study Selection</h3> Peer-reviewed intervention studies published in English, conducted in adult patients with primary CNS infections were considered eligible. Three researchers independently assessed study titles and screened abstracts for inclusion criteria. <h3>Data Extraction</h3> Study quality was assessed independently by two researchers using the National Institutes of Health quality assessment tools for randomized controlled trials (RCTs) and pre-post intervention studies. Data extraction included characteristics of participants, infectious agents, interventions, and measures used to study cognitive outcomes. <h3>Data Synthesis</h3> Nine studies of varying quality (two of high quality, the rest of fair quality), eight of which were RCTs and one pre-post intervention study, reported on the effectiveness of drug(s) on cognitive outcomes in adult patients with Lyme disease (LD; five studies), Herpes Simplex Virus Type 1 (HSV-1; three studies), and Creutzfeldt-Jakob disease (CJD; one study). In patients with LD, the studies reported inconsistent results on the effectiveness of antibiotics' therapy on enhancing cognitive outcomes; the type of drug, route, and duration of administration varied. In patients with HSV-1, antiviral drugs alone, or in combination with antipsychotics, showed that the drug alone or in combination enhanced certain cognitive domains, but not all, compared to placebo. The single study on patients with CJD demonstrated that a non-opioid drug flupirtine maleate, possessing analgesic and muscle relaxant properties, enhanced baseline cognitive performance. <h3>Conclusions</h3> Evidence on the ability of pharmaceutical therapy enhancing cognitive deficits in patients with LD, HSV-1, and CJD is limited and inconclusive. The repeated searches for the period from November 2019 until current, once identified and assessed, may alter the conclusions of the review. Future research should evaluate the meaningfulness of cognitive change in patients with primary CNS infections. <h3>Author(s) Disclosures</h3> None to Disclose.