Background: Elucidating the influence of mild intellectual disability (MID; IQ 50-70)/borderline intellectual functioning (BIF; IQ 70-85) and (comorbid) post-traumatic stress disorder (PTSD) on the quality of life of patients with serious mental illness (SMI) could improve their mental health care. Method: This study comprises a prospective longitudinal cohort study using routine outcome monitoring data. The cohort comprised 601 patients who had undertaken at least one Manchester Short Assessment of Quality of Life (MANSA). The scores for screeners to detect MID/BIF and PTSD were analysed, and a repeated measures analysis of variance and a multi-level linear regression was performed on the MANSA scores. Results: The average quality of life for all patient groups increased significantly over time. A between-subject effect on quality of life was observed for PTSD, but not MID/BIF. Conclusions: PTSD but not MID/BIF is associated with a lesser quality of life over time.