Illness intrusiveness derives from illness-induced lifestyle disruptions that interfere with continued involvements in valued activities and interests and is hypothesized to represent a fundamental determinant of the psychosocial impact of chronic conditions. The present investigation compared reported levels of illness intrusiveness across 305 individuals from three chronically ill populations: rheumatoid arthritis (N = 110), end-stage renal disease (N = 101), and multiple sclerosis (N = 94). Although multiple sclerosis was significantly more intrusive, overall, into lifestyles, activities, and interests as compared with rheumatoid arthritis and end-stage renal disease (which did not differ), a significant illness group x life domain interaction indicated that intrusiveness into eight individual life domains differed significantly across the groups and that the pattern of differences varied as a function of the particular life domain involved. Differences in the constellations of signs, symptoms, and treatment regimens associated with a given condition were hypothesized to account for observed differences in illness intrusiveness.