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Chronic illnesses and social isolation are major public phenomena that drive health and social policy worldwide. This article describes a middle-range theory of social isolation as experienced by chronically ill individuals. Key concepts include social disconnectedness, loneliness, and chronic illness. Antecedents of social isolation include predisposing factors (e.g., ageism and immigration) and precipitating factors (e.g., stigma and grief). Outcomes of social isolation include psychosocial responses (e.g., depression and quality of life), health-related behaviors (i.e., self-care), and clinical responses (e.g., cognitive function and health service use). Possible patterns of social isolation in chronic illness are described.