Abstract Introduction Cachexia is a progressively debilitating loss of skeletal muscle often seen in late-stage chronic medical diseases, such as cancer, HIV/AIDS, chronic obstructive pulmonary disease (COPD), and liver cirrhosis. Cachexia contributes to mortality and morbidity with reduced quality-of-life (QoL) and disease treatment options, and can be associated with adult-onset hypogonadism (AOH), which is commonly treated with testosterone replacement therapy (TRT) in men. Objective This comprehensive review highlights the current literature on TRT for management of patients with chronic disease-associated cachexia, with an emphasis on clinical outcomes and side effects. Specifically, we identify and highlight relevant primary literature and reviews published since 2000 on TRT for management of patients with cancer, COPD, HIV/AIDS, and liver cirrhosis. Methods A comprehensive PubMed literature review was performed to identify articles published between 2000-2021 on TRT and cachexia-related chronic medical diseases (cancer, COPD, HIV/AIDS, and liver cirrhosis) to highlight the use of TRT for management of AOH in male patients with cachexia. The list of studies generated by the initial search was screened to identify eligible studies. Inclusion criteria included primary literature with clinical outcome measures related to changes in lean body mass, muscle mass, body composition, QoL, fatigue scores, and/or exercise scores, in addition to relevant meta-analyses. Results 12 studies were included in our review out of 653 initial search results (Table 1). In three studies of TRT in cancer patients, there were mixed results on the effects of TRT on QoL assessment. Across three studies of TRT in COPD patients, there was consistent improvement in exercise capacity and disease condition with TRT. Across four studies of TRT in HIV-infected men, TRT resulted in notable improvement in body weight, muscle mass, function, and QoL. Lastly, in two studies of TRT in patients with cirrhosis, testosterone therapy improved muscle strength and body composition across both cohorts. Conclusions Based on recent studies, there is robust data for the clinical benefits of TRT for the management of certain subgroups of cachexic patients, specifically those with COPD, HIV, and liver cirrhosis. Because of mixed results in cancer cachexia patients, further investigation of its long-term efficacy is warranted, in addition to hormonal therapy for female cachexic patients. Disclosure No