Objective:To investigate the efficacy of antiviral therapy and its selection in hospitalized children with infectious mononucleosis (IM).Methods:The IM children admitted to Shenzhen Children’s Hospital from January 2017 to December 2021 were divided into acyclovir (ACV) treatment group and non-antiviral treatment group, and the clinical data were collected for retrospective analysis.Results:A total of 370 children were included, the median age was 3.6 years, each age group proportion: <3 years (25.9%), 3-<6 years (53.0%). 6-<10 years (17.6%) and ≥10 years (3.5%). Male∶Female=1.5∶1. While 42.4% (157/370) of the 370 children received ACV, 57.6% (213/370) did not receive antiviral therapy; 52 cases were treated in infectious disease department, and none of them received antiviral treatment, and 318 cases were treated in non-infectious disease department, of which 157 cases were in ACV group. There was significant difference between the two groups ( P <0.001); Thirty-eight cases of children in non-infectious disease department complicated with abnormal liver function, of which 23 cases (60.5%) were in the ACV group and 15 cases (39.5%) were in the non-antiviral treatment group. There was no significant difference between the two groups ( P=0.060). Compared with the non-antiviral treatment group, the ACV group has longer hospitalization days and higher hospitalization expenses ( P<0.01). There was no significant difference in duration of fever ( P>0.05). The number of atypical lymphocytes recovered faster in ACV group ( P=0.001). Conclusions:The hospitalized children with IM were mostly boys, and most of them were from 3 to 6 years old. ACV treatment could not shorten the duration of fever and hospitalization days of IM children, nor could it reduce the hospitalization expenses. Abnormal liver function did not affect the decision of antiviral treatment, and infectious disease specialists prefer not to use antiviral drugs. The authors advocate reducing the use of antiviral drugs for IM.