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Background The increase of adolescent multimorbidity in welfare states is a major concern for current and future population health. However, current health interventions remain insufficient. Syndemic research among adolescents in high-income countries could improve understanding of mechanisms contributing to social and health inequalities.This study explores the existence of clustered health conditions among adolescents aged 10–19 registered at general practices in two average Dutch cities: The Hague and Leiden. We examine which social and contextual factors are associated with these clustered health conditions and to what extent these clusters relate to healthcare use and costs.Methods This cross-sectional study used general practitioner registration data on diagnoses from the Extramural Leiden University Medical Centrum Academic Network database to explore multimorbidity based on the 2-year prevalence of 20 health conditions among adolescents (n=10 841). Latent class analysis was applied to distinguish multimorbidity classes. Statistics Netherlands provided information on factors at the individual (eg, country of origin), family (eg, divorced parents) and household (eg, income) levels. Multinomial logistic regression analysis was applied to identify multimorbidity class differences in these social contextual factors, healthcare use and costs.Results In 2018 and 2019, 25.7% (n=2781) of adolescents had at least two health conditions. We identified four classes characterised by a high probability of health conditions: ‘asthma-skin conditions’ (n=442), ‘skin conditions-pain’ (n=794), ‘externalising behavioural disorders and skin conditions’ (n=565) and ‘gastrointestinal conditions, internalising disorders and pain’ (n=980). Adolescents in classes characterised by externalising or internalising conditions combined with physical and somatic health conditions were most often linked to several more prominent adverse social contextual factors, such as early school dropout. Increased healthcare use and costs across all classes indicated a higher disease burden for adolescents with clustered health conditions compared with those with one or no health conditions.Conclusions Disease clusters are prevalent in adolescents living in Dutch cities, driven by social contextual factors at the individual, household and parental levels, and show increased healthcare use and costs. Our results support the need for integrated preventative strategies focusing on multi-level aspects.