Mycophenolate mofetil (MMF) is an immunosuppressive agent that has been shown to be effective in transplant patients. Some case reports and pilot studies have suggested efficacy against systemic lupus erythematosus (LE), particularly in the case of lupus nephritis. Reports on MMF treatment of skin manifestations of LE are still anecdotal. We report two cases with extensive skin lesions owing to subacute cutaneous LE (SCLE). Both patients had been treated with azathioprine and antimalarials without effect. Finally both patients were given highly dosed glucocorticosteroids, which were also ineffective but led to vertebral fractures because of long-term steroid treatment in one patient and steroid-induced psychosis in the other. MMF 2 g daily caused the skin manifestations to disappear within a few weeks in both patients. One patient was followed up for more than 24 months, and showed good toleration of MMF treatment. The skin remained stable over this period when at least 1 g MMF per day was administered. In conclusion, MMF appears to be an attractive treatment option in skin manifestations of SCLE, and seems to be beneficial for patients with steroid-refractory lesions that are also resistant to treatment with immunosuppressants or antimalarials. The observations suggest that further evaluation of this route in randomized controlled trials is warranted.