Evidence shows that psychosocial problems among children and adolescents with asthma interfere with adherence to treatment and therefore need attention in asthma care. It is unknown whether the already frequently implemented asthma-related quality of life (QoL) instruments reflect psychosocial problems in children with asthma. The aim of this study was to assess the relationship between asthma-related QoL and psychosocial problems and to determine whether an asthma-related QoL instrument is able to identify those children and adolescents with asthma with major psychosocial problems. In a multicenter study psychosocial problems (Strengths and Difficulties Questionnaire) and asthma-related QoL (Pediatric Asthma (Caregivers) Quality of Life Questionnaire) were obtained in children and adolescents with asthma aged 6-16 years and their caregivers. A total of 339 children and adolescents (response rate 95%) from four pediatric outpatient clinics in the Netherlands with doctor-diagnosed asthma participated. Of the caregivers, 43% reported major or minor psychosocial problems of their child or adolescent which is two times more than in the reference group, whereas the percentage of adolescents reporting psychosocial problems was comparable to a reference population. Adolescents and caregivers reported few impairments in asthma-related QoL (median score between 6.2 and 7.0). However, an optimal asthma-related QoL did not rule out major psychosocial problems: 10% of the adolescents with an optimal asthma-related QoL score reported major psychosocial problems. And in one out of seven children with an optimal caregiver's asthma-related QoL score, major psychosocial problems were reported. The prevalence of psychosocial problems in children and adolescents with asthma is considerable. Assessment of asthma-related QoL alone is insufficient to identify those children with major psychosocial problems. We recommend the implementation of psychosocial screening, besides assessment of asthma-related QoL, in routine pediatric asthma care, to improve asthma management.