Mycophenolate mofetil (MMF) is a highly effective adjunct immunosuppressive agent in transplant therapy. Although MMF is generally well tolerated, optimal therapy may be limited by adverse effects. MMF dose changes resulting from these adverse events may lead to sub-therapeutic dosing and impaired clinical outcomes. We conduct this study to determine whether MMF dose reduction after renal transplantation is associated with subsequent risk of acute rejection. This retrospective study analyzed clinical records from 558 renal transplant patients from two Iranian transplant centers who were initiated on MMF. One hundred seventy nine patients (32%) had MMF dose reductions during the study. MMF dose was reduced because of gastrointestinal symptoms (32.9%), bone marrow suppression (28.4%) infection (20.7%), malignancy (2.3%), and unknown reasons (15.7%). The cumulative number of days with the MMF dose reduced below full dose was an independent predictor of acute rejection. The relative risk of rejection increased by 3.6% for every week that the MMF dose was reduced below full dose. No significant association was observed between the number of days with MMF dropped below full dose and allograft failure. The cumulative number of days with the MMF dose dropped below full dose is a significant predictor of acute rejection after renal transplantation. Clinicians need to be aware of the rejection risk when the MMF dose is reduced and maintain close surveillance on such patients.