BACKGROUND Non-Hodgkin lymphoma is the most common hematological malignancy in the world. Diffuse large B-cell lymphoma the most common type and the cutaneous involvement due to this neoplasm is rare. Some risk factors, such as exposure to pesticides, alcohol consumption, and tobacco use, are well established. Over the past 10 years, the association between clozapine, which is the criterion standard treatment for refractory schizophrenia, and hematological malignancies has been described. CASE REPORT We report a case of a 44-year-old woman diagnosed with schizophrenia 31 years previously, who had been taking clozapine since 2009, presenting with diffuse cutaneous nodules and subcutaneous masses accompanied by asthenia, dry cough, and a weight loss of 12 kg. Computed tomography revealed multiple enlarged lymph nodes on both sides of the diaphragm, in addition to multiple large subcutaneous masses located on the right flank and on the right upper lateral chest wall (infra-axillary), homogeneous splenomegaly, and heterogeneous nodular areas of hypoenhancement, poorly delimited, in both kidneys. Diffuse large B-cell lymphoma in an advanced stage (IVBX) was diagnosed by skin biopsy, with extranodal involvement. Chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days) was performed and the decision to maintain clozapine was made. At 1.5 years after the initial diagnosis the patient presented with relapse of the disease and is in follow-up. CONCLUSIONS This case report suggests the potential association between clozapine and an increased risk of lymphoma, with a few case reports in the literature reinforcing this association. Additional studies are required to either confirm or dismiss this association, and new guidelines are needed to define the safety and monitoring of the long-term usage of clozapine.