Abstract Background Opioid use is a major public health concern across the globe. Opioid use and subsequent access to care is often shaped by co-occurring issues faced by people using opioids, such as deprivation, mental ill-health, and other forms of substance use. We investigated the role of social deprivation and comorbid mental health diagnoses in predicting re-engagement with substance use services or contact with crisis and inpatient services for individuals with opioid use disorder in secondary mental health care in inner-city London. Methods We conducted a prospective cohort study which followed individuals diagnosed with a first episode of opioid use disorder who accessed substance use services between September 2015 and May 2020 for up to 12 months, using anonymised electronic health records. We employed negative binominal regression and Cox proportional survival analyses to assess associations between exposures and outcomes. Results Comorbid mental health diagnoses were associated with higher contact rates with crisis/inpatient services among people with opioid use disorder: incidence rate ratios (IRR) and 95% confidence intervals (CI) were 3.91 (1.74–9.14) for non-opioid substance use comorbidity, 8.92 (1.81–64.4) for a single comorbid mental health diagnosis, and 15.9 (5.89–47.5) for multiple comorbid mental health diagnoses. Social deprivation was not associated with contact rates with crisis/inpatient services within this sample. Similar patterns were found with time to first crisis/inpatient contact. Social deprivation and comorbid mental health diagnoses were not associated with re-engagement with substance use services. Conclusion Comorbid substance and mental health difficulties amongst people with an opioid use disorder led to earlier and more frequent contact with crisis/inpatient mental health services during the first 12 months of follow up. Given the common co-occurrence of mental health and substance use disorders among those who use opioids, a better understanding of their wider needs (such as social, financial and other non-medical concerns) will ensure they are supported in their treatment journeys.