Despite therapeutic advances in the treatment of systemic lupus erythematosus (SLE), several patients are still afflicted with severe and uncontrolled symptoms. Recently, mycophenolate mofetil (MMF) has been introduced in the treatment of SLE, with a significant therapeutic benefit, and minor side effects have been reported. Data on the adverse effects of MMF in SLE are lacking. We present an SLE patient who developed urticaria during MMF treatment. Rechallenge with MMF established the diagnosis of MMF-induced urticaria. As MMF was considered a necessary therapy, a desensitization protocol was devised, which successfully induced tolerance to MMF. This is the first published protocol for MMF desensitization, which induced tolerance in an SLE patient previously reacting with generalized urticaria.