Human factors and ergonomics approaches have been successfully applied to study and improve the work performance of healthcare professionals. However, there has been relatively little work in “patient-engaged human factors,” or the application of human factors to the health-related work of patients and other nonprofessionals. This study applied a foundational human factors tool, the systems model, to investigate the barriers to self-care performance among chronically ill elderly patients and their informal (family) caregivers. A Patient Work System model was developed to guide the collection and analysis of interviews, surveys, and observations of patients with heart failure (n=30) and their informal caregivers (n=14). Iterative analyses revealed the nature and prevalence of self-care barriers across components of the Patient Work System. Person-related barriers were common and stemmed from patients’ biomedical conditions, limitations, knowledge deficits, preferences, and perceptions as well as the characteristics of informal caregivers and healthcare professionals. Task barriers were also highly prevalent and included task difficulty, timing, complexity, ambiguity, conflict, and undesirable consequences. Tool barriers were related to both availability and access of tools and technologies and their design, usability, and impact. Context barriers were found across three domains—physical-spatial, social-cultural, and organizational—and multiple “spaces” such as “at home,” “on the go,” and “in the community.” Barriers often stemmed not from single factors but from the interaction of several work system components. Study findings suggest the need to further explore multiple actors, context, and interactions in the patient work system during research and intervention design, as well as the need to develop new models and measures for studying patient and family work.