Pretibial myxedema (PTM) is a rare extrathyroidal manifestation of Graves' disease that requires treatment when the clinical picture is markedly evident. In addition to topical treatment with steroid ointments, there have been previous reports of subcutaneous injections of steroids. This procedure may cause nodular degeneration of the skin due to fat atrophy when standard needles are used. In the present study, we have tried a novel modality of treatment of PTM by injecting a solution of dexamethasone in the subcutaneous tissue using needles employed for mesotherapy. These needles are ≤4 mm long and deliver the medication within the dermis or the first layer of the subcutaneous fat. We have treated five patients, four with diffuse and one with elephanthiasic PTM. We utilized multiple injections of a solution of dexamethasone, lidocaine, and saline in the PTM plaque and in the pretibial area, both in the PTM plaque and in the area surrounding the lesions, once a week for three consecutive weeks. Two patients with a more severe form of PTM underwent another two cycles four to six weeks after initial treatment. Patients were studied before and after treatment by clinical assessment and ultrasound of the pretibial skin. The treatment was well-tolerated, with only moderate pain upon injection of the solution. One month after treatment, all patients showed improvement of PTM at clinical assessment and a reduction of the thickness of the lesions at ultrasound of ∼15%, involving mostly the dermis. Moreover, all patients reported amelioration of the leg appearance. The present study, although preliminary, shows that intralesion steroid injection with mesotherapy needles in PTM is effective and well tolerated, and does not cause undesired long-term modifications of the skin. More studies are warranted to standardize such treatment in larger groups of patients.