BackgroundIn order to target the complex health needs of patients with multimorbidity using psychoactive substances, knowledge regarding the association between substance use and multimorbidity in an acute setting is needed.AimsExamine psychoactive substance use patterns among acute medically ill patients, and determine the association between multimorbidity and substance use, and psychological distress.DesignCross-sectional study.Setting and participants2874 acute medically ill patients admitted to a medical emergency department in Oslo, Norway.MeasurementsPrimary outcome: multimorbidity recorded by the presence of ≥2 International Classification of Diseases 10th revision—physical and/or mental health conditions per patient, extracted from medical records. Predictor variables: self-reported data on age, sex, occupational status, psychological distress (Hopkins Symptom Check List-5), alcohol use (Alcohol Use Disorder Identification Test-4) and results from blood samples on psychoactive medicinal and illicit drugs.FindingsOf all patients, 57.2% had multimorbidity. Of these, 62.6% reported psychological distress, 85.5% consumed either alcohol, medicinal and/or illicit drugs and 64.4% combined alcohol with psychoactive medicinal drugs. Patients with risky alcohol use were more likely to have multimorbidity compared with patients with low-risk alcohol use (OR 1.53; 95% CI 1.05 to 2.24). Patients using psychoactive medicinal drugs were more likely to have multimorbidity compared with non-users (OR 1.34; 95% CI 1.07 to 1.67).ConclusionMultimorbidity was associated with psychoactive medicinal drug and risky alcohol use, and psychological distress. Substance use was widespread, with alcohol and psychoactive medicinal drugs most frequently combined. Monitoring substance use among multimorbid patients is necessary to develop tailored treatments, and reduce burden on the healthcare system.