Background: Patients with co-existence of psychiatric disorders and substance use have an increased risk of premature death. This is attributable to a higher prevalence of physical comorbidities and a lifestyle related to substance use. Furthermore, they experience low quality-of-life (QoL). Studies addressing lifestyle interventions for these patients are warranted.Aims: To investigate the physical health and QoL in patients with co-existence of psychiatric disorders and substance use, and to analyse for changes in their (a) health, (b) substance use, and (c) QoL after a 24-month health-promotion programme. Further aims were to investigate associations between (a) QoL and number of interventions, (b) QoL and patient characteristics, and (c) QoL and length of participation in the intervention.Methods: In this naturalistic cohort study, 64 non-selected patients were engaged in health-promoting interventions added to contemporary treatments. QoL and clinical variables were measured at the beginning of and continuously during the programme by means of the WHOQoL-Bref questionnaire.Results: At enrolment, the patients' intake of cannabis and alcohol was high. During follow-up, patients consumed significantly fewer caffeinated beverages (p=.038) and fast-food meals (p=.018), and slept significantly less (p=.032). The average dose of antipsychotic medication increased significantly (p=.015). QoL was low at enrolment, but improved significantly overall (p=.009) and in the psychological (p=.020) and environmental domains (p=.012) at follow-up. The difference in total QoL was positively associated with the number of interventions attended.Conclusion: This programme shows promise in addressing health promotion for these patients and can easily be integrated into contemporary treatments.