Extranodal non-Hodgkin lymphomas (NHLs) arising in soft tissue is rare. This study describes a rare case of chemo-resistant large B-cell NHL of skeletal muscle, characterized by voluminous swelling in the thigh which responded well to radiotherapy. In this patient, recurrent NHL showed refractoriness to various chemotherapy regimens and was treated with radiation therapy repeatedly with excellent local response and no evidence of disease for 18 months. Most of the published literature describes surgery or chemotherapy as treatment for NHL soft tissue. This is the first case report describing the durable response with radiation without in-field recurrence in chemo-resistant large B-cell NHL skeletal muscle.