Approximately 10% of children grow up with a parent who has been diagnosed with a chronic medical condition (CMC) and seem to be at risk for adjustment difficulties. We examined differences in behavioral, psychosocial and academic outcomes between 161 adolescents from 101 families with a chronically ill parent and 112 adolescents from 68 families with healthy parents, accounting for statistical dependence within siblings. Children between 10 and 20 years and their parents were visited at home and filled in questionnaires. Multilevel analyses showed that 20–60% of the variance in most adolescent outcomes was due to the family cluster effect, especially in internalizing problem behavior, caregiving variables and quality of parent attachment. Conversely, the variance in stress and coping variables and grade point average (GPA) was mainly due to individual characteristics. Adolescents with parents affected by CMC displayed more internalizing problems than the comparison group and scored higher on frequency of household chores, caregiving responsibilities, activity restrictions, isolation, daily hassles and stress. In addition, their grade point average was comparatively worse. No group differences in externalizing problems, coping skills and quality of parent attachment were found. In conclusion, the family cluster effect largely explains adolescent outcomes and should be accounted for. Adolescents with parents affected by CMC are subject to an increased risk for internalizing problems, adverse caregiving characteristics, daily hassles, stress and a low GPA. According to a family-centered approach, school counselors and health care practitioners should be alert to adjustment difficulties of children with a chronically ill parent.