<p>To investigate the proportion of patients with infectious mononucleosis who develop a rash after antibiotic administration, primarily aminopenicillins, and to examine the association between antibiotic use and the risk of rash. PubMed, Cochrane Library, and Google Scholar were searched from inception to 09/2024. The quality of the studies was evaluated using the Newcastle-Ottawa scale. A primary and secondary meta-analysis of proportions and odds ratios, respectively, was conducted with random-effect models. In total, 15 observational studies (6 during 1967–1976 and 9 during 2012–2024, with 3153 patients) and 34 case reports were evaluated. The pooled estimate of the proportion of patients with infectious mononucleosis who developed a rash after administration of an aminopenicillin was 43% (95% CI 18–72%), 15% (95% CI 10–22%) after administration of other antibiotics, and 14% (95% CI 10–19%) after no antibiotic use. In subgroup analysis by publication year, the pooled estimate of the proportion of patients with a rash after aminopenicillin was 84% (95% CI 67–93%) in old studies (1967–1976) and 18% (95% CI 10–30%) in recent studies (2012–2024). The secondary analysis showed a significantly increased risk of rash associated with aminopenicillin (OR 5.4, 95% CI 1.8–16.3; I² = 89%) compared to no antibiotic use. Sensitivity analyses based on the patient’s age and the Newcastle-Ottawa scale did not reduce the high heterogeneity. This study demonstrated that the occurrence of rash in patients with infectious mononucleosis after administration of an aminopenicillin is much lower than the medical community believes.</p>