Background: Children of parents with mental illness have an elevated risk of developing a range of mental health and psychosocial problems. Yet many of these children remain mentally healthy. Objective: The present study aimed to get insight into factors that protect these children from developing internalizing and externalizing problems. Methods: Several possible individual, parent-child, and family protective factors were examined cross-sectionally and longitudinally in a sample of 112 adolescents. A control group of 122 adolescents whose parents have no mental illness was included to explore whether the protective factors were different between adolescents with and without a parent with mental illness. Results: Cross-sectional analyses revealed that high self-esteem and low use of passive coping strategies were related to fewer internalizing and externalizing problems. Greater self-disclosure was related to fewer internalizing problems and more parental monitoring was related to fewer externalizing problems. Active coping strategies, parental support, and family factors such as cohesion were unrelated to adolescent problem behavior. Longitudinal analyses showed that active coping, parental monitoring, and self-disclosure were protective against developing internalizing problems 2 years later. We found no protective factors for externalizing problems. Moderation analyses showed that the relationships between possible protective factors and adolescent problem behavior were not different for adolescents with and without a parent with mental illness. Conclusions: The findings suggest that adolescents' active coping strategies and parent-child communication may be promising factors to focus on in interventions aimed at preventing the development of internalizing problems by adolescents who have a parent with mental illness.