Background: Acyclovir has been widely used to treat infections caused by herpes simplex virus (HSV) and varicella zoster virus (VZV). The common adverse effects of this drug include nausea, diarrhea, headache, dizziness and mental changes. The immune thrombocytopenia induced by acyclovir is rare. Case presentation: A 67-year-old Chinese male who was given acyclovir 5 mg kg(-1) 8 hourly intravenously for treatment of VZV infection developed severe thrombocytopenia with fist sign in oral cavity within 10 days of starting using acyclovir. The patient's condition was improved by stopping using acyclovir and further supportive treatment. The acyclovir-dependent platelet antibody test showed positive results, which implicated acyclovir as the causative agent. The final definitive diagnosis of acyclovir-induced immune thrombocytopenia was established basing on the time correlation between the start of using acyclovir and the onset of symptoms of thrombocytopenia, combining with excluding of other common causes of thrombocytopenia. Conclusion: There have been few reports of acyclovir-induced immune thrombocytopenia. This is the first case report and literature review of acyclovir-induced immune thrombocytopenia, with tongue hematoma as the first sign. Dentists should never overlook this rare adverse effect of acyclovir, as a rapid and appropriate treatment may prevent further severe life-threatening complications.