Direct-acting antiviral agents (DAAs) have been the mainstream treatment of hepatitis C because of tolerability and efficacy. A 67-year-old man presented with acute drowsiness preceded by headache after starting DAAs (sofosbuvir and velpatasvir) for treatment of hepatitis C. Herpes zoster and herpes simplex stomatitis were noted. Later, HSV-1 encephalitis was diagnosed based on positive HSV1-PCR of CSF, while other tests were negative including HSV2-PCR, syphilis, culture of bacteria, tuberculosis and fungus. Further study showed the presence of concomitant Sjögren syndrome. The patient recovered well with the combination of intravenous acyclovir and steroid. Immune reconstitution inflammatory response (IRIS) may be the most important mechanism of this patient’s severe illness. In conclusion, severe CNS infection instead of just peripheral nervous system involvement may occur due to herpes virus reactivation caused by DAAs. Screening of autoimmune markers may be considered before DAA therapy