Sofosbuvir and simeprevir are used for the treatment of chronic hepatitis C (HCV) genotype 1. Both drugs have been well-tolerated, with diarrhea noted in 6% cases with sofosbuvir, 16% with sofosbuvir plus simeprevir, and 0% with simeprevir. No prior reports exist of colitis secondary to either drug or their combination. We report a patient with no prior history of inflammatory bowel disease who developed significant bloody diarrhea within 2 weeks of sofosbuvir/simeprevir initiation. Colonoscopy and biopsy confirmed pancolitis, which responded to mesalamine and completion of sofosbuvir/simeprevir.