Objective: To evaluate the clinical efficacy and safety of Chinese drugs for the treatment of children's infectious mononucleosis (CIM). Methods: Sixty CIM patients were assigned into the treated group and the control group, patients in the treated group were administered with Chinese herbal decoction, and those in the control group were treated with intravenous dripping of ganciclovir 10 mg/kg per day, for a treatment course of 14 days. Results: The total effective rate was 96.0% in the treated group and 97.1% in the control group, showing insignificant difference between groups. The efficacy in the treated group was superior to that in the control group on the fever clearance time (3.0 +/- 1.5 days vs 4.9 +/- 3.9 days) and the disappearance time of cervical lymph node swelling (0.8 +/- 1.0 score vs 1.5 +/- 1.2 score), showing statistical significance (all P<0.05). T-cell subsets were markedly improved in both groups after treatment. Adverse reaction occurred in four cases of the control group. Conclusion: Using Chinese herbs for clearing heat, removing toxin, activating blood circulation, and dissolving stasis is effective and safe for the treatment of CIM. It can effectively improve the clinical symptoms and shows a certain effect on immune regulation.