Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is almost universal. The optimal immunosuppression for these patients is still under discussion. We designed a retrospective case-control study to evaluate the effect of mycophenolate mofetil (MMF) treatment in patients with recurrent hepatitis C. Forty patients with histologically proven hepatitis C recurrence after OLT were treated with MMF and calcineurin inhibitor (CNI) taper for 24 months and matched with 40 non-MMF-treated positive liver transplant recipients. Liver biopsies were obtained prior to MMF treatment and after a mean follow-up of 24 months. Histological changes were evaluated utilizing the Metavir score. Comparison of fibrosis/inflammation showed no impairment of histological findings during MMF treatment. In contrast, histological findings of the 40 non-MMF patients showed a significant increase of severity for inflammation/fibrosis. Viral load was similar in both groups. The course of alanin amino transferase (ALT) levels measured during MMF treatment showed a significant decrease. MMF in combination with CNI taper showed a positive effect on fibrosis progression, graft inflammation and ALT levels and may improve the clinical course of HCV after OLT, however, the antiviral properties of MMF are still unconfirmed.