Aims To systematically review the evidence regarding the risk of skin rash in adults treated with amoxicillin with infectious mononucleosis (IM). Methodology We performed a systematic review of the database OVID. The protocol was registered with PROSPERO (registration CRD42023424609). Three studies met inclusion criteria, after screening 1172 articles; two retrospective analyses and one case series. Only one paper statistically analysed results. The papers were compared narratively. Results There was no statistical difference between the use of penicillin (4/47 patients reported rash) and no penicillin (8/66 patients reported rash) in a retrospective cohort study of 113 patients with IM. Similarly, a retrospective cohort study of 46 patients with IM found 1/9 (10%) patients given amoxicillin developed rash compared with 4/37 (11%) who were not. Data from a case series of five patients reported rash in 5 out of 100 patients with EBV, none of whom received penicillin, although there was no control group. Conclusion In summary, the data from adults in our up-to-date review of available case series of more than 5 patients and cohort studies does not support an increased risk of rash in patients with IM dependent on amoxicillin use. This is in concordance with a recent review by Thompson et al. of children and adults including case reports as well as retrospective studies (none of the three reported here due to different inclusion criteria) which concluded most recent data reports a lower rate of rash than historical case report data. Larger prospective studies are required to determine the true rate of skin rash with amoxicillin use, if any, to ensure effective and safe treatment is given to patients.