Tuberous sclerosis (TS) is a rare autosomal dominant genetic multisystem disease caused by mutations in either the TSC1 or TSC2 gene and results in the growth of non-cancerous masses in several organs. Diffuse large B-cell lymphoma (DLBCL) is the predominant non-Hodgkin lymphoma in adolescents and young adults. Metronomic chemotherapy (mCHEMO) can be defined as the frequent, regular administration of drug doses able to maintain a low, but active, range of concentrations of chemotherapeutic drugs during prolonged periods of time. We present the case of a young woman with severe TS who developed DLBCL. She was treated consecutively with the mCHEMO schedule R-DEVEC (prednisone, vinorelbine, etoposide, cyclophosphamide, plus rituximab) and then ibrutinib, achieving an impressive long-lasting complete remission. In conclusion, alternative treatments could be necessary when comorbidities are present in patients, and mCHEMO can be a potential successful therapeutic approach in frail subjects.