Lupus erythematosus panniculitis (LEP) or lupus profundus (LP) is a clinical variant of lupus eryhematosus that involves the deep dermis and the subcutaneous fat and is associated with tender subcutaneous nodules or plaques, with occasional ulceration, atrophy, and scarring. The management of this entity can be difficult because of the lack of response to conventional treatments, such as systemic steroids and antimalarials. The two patients of this study presented LP refractory to several therapies that demonstrated a remarkable improve to the infusion of the anti-CD20 monoclonal antibody, rituximab at a dosage of 375 mg/m2/week. After the first infusion, painful lesions had resolved without the appearance of new lesions. Rituximab may be an effective treatment for patients with LP when other therapies are ineffective. To date, there is only one case report of LEP treated with rituximab in the literature.