Jarisch-Herxheimer reaction (JHR) is a self-limited, acute febrile hypersensitivity reaction that occurs after antibiotic therapy against spirochetes disease. When occurring in the text of syphilis therapy, the JHR begins typically 1-2 hour after the administration of penicillin and is characterized by fever, chills, myalgias, and exacerbation of skin lesions. Rarely, severe JHR can occur in the form of endocarditis, fulminant hepatitis, and hypersensitivity pneumonitis. Recently, we experienced an interesting case of JHR complicated by the hypersensitivity pneumonitis after treating secondary syphilis. Proper differential diagnosis is required to differentiate this reaction from drug-induced hypersensitivity reaction.