Cancer interferes with participation in valued lifestyle activities (illness intrusiveness) throughout post-treatment survivorship. We investigated whether illness intrusiveness differs across life domains among survivors with diverse cancers. Intrusiveness should be highest in activities requiring physical/cognitive functioning (instrumental domain). Intrusiveness into relationship/sexual functioning (intimacy domain) should be higher in prostate, breast, and gastrointestinal cancers than in others. Cancer outpatients (N = 656; 51% men) completed the Illness Intrusiveness Ratings Scale (IIRS) during follow-up. We compared IIRS Instrumental, Intimacy, and Relationships and Personal Development [RPD] subscale and total scores across gastrointestinal, lung, lymphoma, head and neck, prostate (men), and breast cancers (women), comparing men and women separately. Instrumental subscale scores (M(men) = 3.05-3.80, M(women) = 3.02-3.63) were highest for all groups, except prostate cancer. Men with prostate cancer scored higher on Intimacy (M = 3.40) than Instrumental (M = 2.48) or RPD (M = 1.59), p's < .05; their Intimacy scores did not differ from men with gastrointestinal or lung cancer. Women collectively showed higher Instrumental (M = 3.39) than Intimacy (M = 2.49) or RPD scores (M = 2.27), p's < .001, but not the hypothesized group difference in Intimacy. Post-treatment survivors continue to experience some long-term interference with activities requiring physical and cognitive functioning. Sexual adjustment may be of special concern to men when treatments involve genitourinary functioning. Ongoing monitoring with the IIRS to detect lifestyle interference throughout survivorship may enhance quality of life. Screening and intervention should target particular life domains rather than global interference.