Context: Over 31 million Americans live with Type 2 diabetes mellitus (T2DM), including socially vulnerable, low-income and minority populations, many of whom experience additional chronic illnesses. Social determinants of health (SDOH) and medical comorbidities impact the disease-specific work of self-management and contribute to disparities in diabetes-related outcomes. Exploration of the relationship between patients’ experiences of treatment burden, challenges posed by SDOH, and comorbid chronic conditions may identify novel strategies for improving patient-centered care and reducing T2DM-related disparities. Objective: To understand experiences of treatment burden in diabetes self-management and related SDOH challenges faced by patients with comorbid T2DM. Study Design: Qualitative study using semi-structured interviews. Setting: Six urban safety-net primary care clinics. Population studied: 20 patients with T2DM and 1 or more additional chronic conditions who received care at a study clinic at least once in the past 18 months. Outcome Measures: We asked respondents about their experiences with T2DM self-management, treatment burden, and life context when experiencing good and poor control of their diabetes. We used a thematic approach, utilizing deductive and inductive codes, to analyze data. Results: Respondents described SDOH-related burden specifically concerning treatment costs and built environment impacts (e.g. access to fresh foods). We identified an emblematic theme of the phased phenomenon of diabetes management – burden is high at the time of diagnosis and early in illness and decreases over time through individual learning, adaptation, and routinization into daily life. However, ongoing challenges due to SDOH and lack of social and practical supports continued to impact T2DM control, intensifying during times of high stress and external situational demands. Comorbidities affecting physical functioning and mental health were particularly impacted by SDOH resulting in increased burden. Respondents described clinic-based mitigating resources such as outreach, transportation, and support for glucose monitoring technology. Conclusions: Understanding the complex forces influencing treatment burden can guide interventions to optimize diabetes care. Individualized strategies focused on easing burden that are adaptable over the course of chronic illness management may improve outcomes for medically complex and socially vulnerable patients.