Introduction: In Japan, etoposide or sobuzoxane, a type of topoisomerase II inhibitor, is orally administered in patients with lymphoma who cannot tolerate conventional combination chemotherapy. However, the related clinical data remain to be fully summarized.Areas covered: We evaluate the efficacy and toxicity of etoposide and sobuzoxane.Expert opinion: Previous studies on etoposide or sobuzoxane monotherapy, including those among patients who could not tolerate conventional chemotherapy, suggested a favorable overall response rate (ORR) with moderate gastrointestinal or liver/renal toxicity. As for adult T-cell leukemia/lymphoma, a clinical trial with a limited sample size exhibited an ORR of >70%. Remarkably, the percentage of patients with a poor performance status was high among those receiving etoposide/sobuzoxane. Given a lack of randomized studies, etoposide/sobuzoxane might be a therapeutic option for lymphoma in a palliative setting. In the future, prospective trials with a homologous treatment schedule are warranted, in which the association between clinical efficacy and characteristics of lymphomas, such as specific gene alterations, should be elucidated.