Introduction: COPD is a leading cause of death worldwide and linked to occupational exposures. We aimed to explore the link between working-life exposome and new-onset COPD, starting with an exposome-wide association study (ExWAS). Method: We included two European multi-centre population-based cohorts, ECRHS and Constances. ECRHS began in 1992 (participants 20-44 years) with two follow-ups at ~10 and ~20 years. Constances, baseline 2012-2020 (18-69 years), one follow-up at ~4 years. COPD was defined by FEV1/FVC<Lower limit of normal and at least one respiratory symptom, excluding those with COPD at baseline. Cumulative exposure was assessed at each follow-up for 49 occupational exposures using 5 job exposure matrices. The ExWAS was conducted with discrete-time hazard models adjusted for sex, weight, pack-years of smoking, parental asthma, years between follow-up, physical activity and center. Results: Information was available for n=4065, male 51% (ECRHS) and n=5855, male 49% (Constances). In ECRHS we found increased risk of new-onset COPD (adjusted Odds ratios; 95% CI) for exposure to: exhaust fumes (1.12; 1.03-1.21), asbestos (1.13; 1.02-1.24), gas fumes (1.13; 1.1-1.25), biological dust (1.11; 1.0-1.22), heavy lifting (1.13; 1.0-1.25), mineral dust (1.11; 1.0-1.23), and house dust mites (1.07; 1.0-1-15). There was no evidence for effect-modification by asthma status. No clear associations were found for Constances. Conclusion: Occupational exposures was linked to increased risk of COPD in ECRHS only, probably due to an older population and longer time of follow-up compared to Constances. This ExWAS set the stage for the next analytical step, assessing the joint effect of the working life-exposme.Read less <