Abstract Background Access to palliative care is often limited for challenging and vulnerable groups, including persons with substance use disorders. However, with optimized healthcare options and liberal substitution policies, this patient group is likely to increase over the upcoming years, and comorbidities will also influence the need for palliative support. Here, we aim at analyzing characteristics and specific challenges associated with substance use disorders (SUD) in palliative care. Methods We retrospectively reviewed all patients diagnosed with substance use disorder that were treated at our Competence Center Palliative Care within the University Hospital Zurich, Switzerland between 2015 and 2021. Patient characteristics, including age, gender, duration of hospitalization, as well as specific metrics like body mass index, distinct palliative care assessment scores, and in-hospital opioid consumption were retrieved from the electronic patient files. Demographics and clinical data were analyzed by descriptive statistics, and compared to those of a control group of palliative care patients without SUD. An opioid calculator was used to standardize opioid intake based on morphine equivalents for meaningful comparisons. Results The primary characteristics revealed that the majority of individuals were single (56%), had no children (83%), lived alone (39%), and were either unemployed or recipients of a disability pension (in total 50%). Nicotine (89%), opioids (67%), and alcohol (67%) were the most used substances. We identified various comorbidities including psychiatric illnesses alongside SUD (56%), hepatitis A, B, or C (33%), and HIV infection (17%). Patients with SUD were significantly younger (p