BACKGROUND: Intensive care unit (ICU) nurses are highly prone to occupational stress and burnout, affecting their physical and mental health. The occurrence of the pandemic and related events increased nurses' workload and further exacerbated their stress and burnout. This work investigates occupational stress and burnout experienced by ICU nurses working with COVID and non-COVID patients. METHOD: A prospective longitudinal mixed-methods study was conducted with a cohort of ICU nurses working in medical ICU (COVID unit;  = 14) and cardiovascular ICU (non-COVID unit;  = 5). Each participant was followed for six 12-h shifts. Data on occupational stress and burnout prevalence were collected using validated questionnaires. Physiological indices of stress were collected using wrist-worn wearable technologies. Participants elaborated on the causes of stress experienced each shift by completing open-ended questions. Data were analyzed using statistical and qualitative methods. RESULTS: Participants caring for COVID patients at the COVID unit were 3.71 times more likely to experience stress ( < 0.001) in comparison to non-COVID unit participants. No differences in stress levels were found when the same participants worked with COVID and non-COVID patients at different shifts ( = 0.58) at the COVID unit. The cohorts expressed similar contributors to stress, based in communication tasks, patient acuity, clinical procedures, admission processes, proning, labs, and assisting coworkers. CONCLUSION: Nurses in COVID units, irrespective of whether they care for a COVID patient, experience occupational stress and burnout.