Syphilis is a complex, systemic infectious disease caused by Treponema pallidum subspecies pallidum. Herein, we report a rare case of secondary syphilis with probable neurosyphilis that was misdiagnosed as pityriasis lichenoides et varioliformis acuta (PLEVA) in a 12-year-old human immunodeficiency virus (HIV) negative patient. A female patient presented to our hospital with a four-month history of relapsed systemic rash, accompanied by hair loss, arthralgia and fatigue. Based on physical examination and skin biopsy, she was initially diagnosed as PLEVA and treated both locally and systemically but failed to present a dermatologic improvement. The diagnosis of secondary syphilis with probable neurosyphilis was made based on serologic and cerebrospinal fluid tests. After neurosyphilis therapy, the clinical manifestations of the patient were significantly improved. Physicians should be alert for the possibility of syphilis when encountering cases with unusual clinical manifestations.