We herein describe the case of a 42-year-old man who developed severe hepatitis caused by hepatitis C virus (HCV) infection at 14 years after the start of human immunodeficiency virus (HIV) treatment. Surprisingly, the levels of alanine aminotransferase (ALT) fluctuated, reaching a peak higher than 1,000 IU/L during chronic HCV infection, and the hepatic histology showed advanced liver fibrosis at 3 years after the primary HCV infection. He was treated with simeprevir, peginterferon-alpha, and ribavirin with a sustained viral response. We conclude that HCV/HIV co-infected patients need to commence anti-HCV therapy when the levels of ALT fluctuate severely under successful HIV control.