Background: The success of cancer therapy is usually compromised by oral complications such as oral herpes simplex virus (HSV) infection, which can affect cancer treatment progression and the patient's quality of life. This network metaanalysis aimed to identify the best antiviral agent to prevent or treat oral HSV in patients being treated for cancer. Methods: A network meta-analysis was performed on the data from randomized controlled trials that assessed antiviral agents for preventive or therapeutic activity versus placebo, no treatment, or any other active intervention in patients being treated for cancer. A search was conducted for trials published since inception until the 10th of May 2020 in three databases: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. The primary outcome was the incidence of oral HSV infection. The agents were ranked according to their effectiveness in the prevention of oral HSV using surface under the cumulative ranking (SUCRA). GRADE was used to assess the certainty of the evidence. Results: Out of 1883 reviewed articles, 16 articles met the inclusion criteria. The pooled relative risk (RR) to develop oral HSV infection in acyclovir group was RR 0.17 (95% CI: 0.10, 0.30), compared to 0.22 (95% CI: 0.06, 0.77) in the valacyclovir group. Acyclovir ranked highest for the prevention of oral HSV (SUCRA 83%) followed by valacyclovir (SUCRA 66 %). Subgroup analysis with different acyclovir regimens revealed that the best regimens in terms of HSV-1 prevention were acyclovir 750 mg/m2 intravenously followed by 1600 mg per day orally, and 800 mg per day orally. Acyclovir 250 mg/m2 per day intravenously was the least effective against the prevention of oral HSV. The quality of evidence was high-moderate based on GRADE approach. Subgroup analysis could not be performed for valacyclovir due to the limited number of studies. Conclusion: Acyclovir is superior to valacyclovir in the prevention oforal HSV infection for patients being treated for cancer as per the current evidence. Further studies are recommended for valacyclovir to identify the dosing regimen that is most effective. These results can help clinicians in decision making; and can also be used to develop guidelines. Keywords: Herpes simplex virus, cancer, antiviral, prophylaxis, systematic review, network meta-analysis.