To determine the safety of a combination of mycophenolate mofetil (Cellcept®, MMF) and IFNβ-1a (Avonex®) in relapsing-remitting multiple sclerosis (RRMS) and to evaluate the effects of the combination on clinical and magnetic resonance imaging (MRI) measures of disease activity. Secondary objectives were clinical and MRI data. An open-label, single-centre study including 30 RRMS patients was performed. Inclusion criteria were patients expanded disability status scale (EDSS) score <6.0, treated by Avonex® for at least 6 months, with at least two relapses during the previous 2 years and at least one during the previous 6 months. MMF at a progressive dose of 2 g per day orally was added to Avonex® for a duration of 6 months. MRI data were obtained at baseline and at the end of the study. The pre-study annual relapse rate was 2.0 ± 0.7 and the EDSS score at baseline was 2.9 ± 1.3. Eleven patients had gadolinium (Gd)-enhanced lesions at baseline for a total number of 35 lesions. Two patients interrupted the combination, one after the first dose for personal reasons unrelated to the study and the other due to diarrhoea. A few of the patients also reported nausea and abdominal pains. Adverse events included benign infectious diseases, insomnia and dizziness. No significant biological abnormalities were noted. The annualized relapse rate was 0.57 ± 0.3 at the end of the study (P < 0.001). The mean EDSS score was 2.6 ± 1.5 and no Gd-enhanced lesions were detected on MRI at the end of the study. MMF and IFNβ-1a (Avonex®) combined therapy is safe and very well-tolerated. Clinical and MRI data suggest that this combination may be beneficial.