Mycophenolate mofetil (MMF) is an immunosuppressive agent that is widely used in the management of liver transplant recipients. MMF inhibits the inosine monophosphate dehydrogenase that has been shown to have in vitro antiviral properties against flaviviruses, suggesting the possibility that it might also inhibit the hepatitis C virus (HCV). The goal of this short-term dose escalation study was to assess the antiviral effects of MMF on HCV replication. Patients with chronic hepatitis C who had not undergone liver transplantation were randomized to 8 weeks of treatment with one of four mycophenolate dose regimens (1000 mg orally twice daily, 500 mg orally twice daily, 250 mg orally twice daily, or a matched oral placebo twice daily). All groups were double-blinded. Quantitative HCV RNA levels and serum alanine aminotransferase were assessed at baseline, at weeks 2, 4, and 8 of dosing, and at weeks 4 and 8 of follow-up. Thirty patients met inclusion criteria, enrolled, and were randomized. HCV RNA levels did not change significantly during treatment. Specifically, no subject became virus negative or had a one-log decrease in virus level. Serum aminotransferase level did not normalize in any subject. The most common side effects were headache, nausea, and diarrhea. Mycophenolate alone does not appear to have a significant antiviral or biochemical effect in patients with chronic hepatitis C.