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RATIONALE While previous studies in environmental epidemiology have focused on single or a few exposures, a holistic approach combining multiple preventable risk factors is needed to tackle the etiology of multifactorial diseases such as asthma. OBJECTIVE To investigate the association between combined socioeconomic, external environment, early-life environment, lifestyle-anthropometric factors and asthma phenotypes. METHODS A total of 20,833 adults from the French NutriNet-Santé cohort were included (mean age: 56.2 (sd: 13.2), 72% women). The validated asthma symptom score (continuous) and asthma control (never-asthma, controlled asthma and uncontrolled asthma) were considered. The exposome (n=87 factors) covered four domains: socioeconomic, external environment, early-life environment and lifestyle-anthropometric. Cluster-based analyses were performed within each exposome domain and the identified profiles were studied in association to asthma outcomes in negative binomial (asthma symptom score) or multinomial logistic (asthma control) regression models. RESULTS In total, 5,546 (27%) individuals had an asthma symptom score ≥1, and 1,206 (6%) and 194 (1%) had controlled and uncontrolled asthma, respectively. Three early-life exposure profiles ("high passive smoking-own dogs", "poor birth parameters-daycare attendance-city center" or "≥2 siblings-breastfed" compared to "farm-pet owner-molds-low passive smoking") and one lifestyle-anthropometric profile ("unhealthy diet-high smoking-overweight" compared to "healthy diet-non-smoker-thin") were associated with more asthma symptoms and uncontrolled asthma. CONCLUSION This large-scale exposome-based study revealed early-life and lifestyle exposure profiles that were at risk for asthma in adults. Our findings support the importance of multi-interventional programs for the primary and secondary prevention of asthma including control of specific early-life risk factors and promotion of healthy lifestyle in adulthood.