Objectives Elevated mortality has been observed among individuals with opioid use disorder (OUD) treated in addiction specialty clinics or programs. Information about OUD patients in general healthcare settings is needed in light of the current effort to integrate addiction services into primary healthcare systems. This study examined mortality rates, causes of death, and associated risk factors among patients with OUD in a large general healthcare system. Methods Mortality data were linked with electronic health records of 2,576 OUD patients cared for in a large university health system from 2006–2014. Results There were 465 deaths confirmed (18.1% of the study participants), corresponding to a crude mortality rate of 48.6 per 1000 person-years and standardized mortality ratio of 10.3 (95% CI, 9.4–11.3). Drug overdose and disorder (19.8%), cardiovascular diseases (17.4%), cancer (16.8%), and infectious diseases (13.5%, including 12% hepatitis C virus [HCV]) were the leading causes of death. HCV (HR: 1.99; 95% CI, 1.62– 2.46) and alcohol use disorder (HR: 1.27; 95% CI, 1.05–1.55) were two clinically important indicators of overall mortality risk. Tobacco use disorder (AHR: 2.58; 95% CI, 1.60–4.17) was associated with increased risk of cardiovascular death, HCV infection (AHR: 2.55; 95% CI, 1.52–4.26) with cancer mortality risk, and HCV (AHR: 1.92; 95%CI, 1.03–3.60) and alcohol use disorder (AHR: 5.44; 95% CI, 2.95–10.05) with liver-related mortality risk. Conclusions Patients with OUD in a general healthcare system demonstrated alarmingly high morbidity and mortality, which challenges health care systems to find innovative ways to identify and treat patients with substance use disorder.