A wide array of risk factors for problem behavior in adolescents with chronically ill parents emerges from the literature. This study aims to identify those factors with the highest impact on internalizing problem behavior (anxious, depressed and withdrawn behavior, and somatic complaints) and externalizing problem behavior (aggressive and rule-breaking behavior) as measured by the Youth Self-Report (YSR). The YSR was filled in by 160 adolescents (mean age = 15.1 years) from 100 families (102 chronically ill parents and 83 healthy spouses). Linear mixed model analyses were used, enabling separation of variance attributable to individual factors and variance attributable to family membership (i.e., family cluster effect). Predictors were child, parent, illness-related and family characteristics. The results showed that almost half of the variance in internalizing problem scores was explained by family membership, while externalizing problems were mainly explained by individual factors. Roughly 60 % of the variance in internalizing problems was predicted by illness duration, adolescents’ feeling of isolation, daily hassles affecting personal life and alienation from the mother. Approximately a third of the variance in externalizing problems was predicted by adolescents’ male gender, daily hassles concerning ill parents and alienation from both parents. In conclusion, the variance in adolescent problem behavior is largely accounted for by family membership, children’s daily hassles and parent–child attachment. To prevent marginalization of adolescents with a chronically ill parent, it is important to be alert for signs of problem behavior and foster the peer and family support system.