The CORDELIA Study (Collaborative Cohorts Reassembled Data to Study Mechanisms and Long-term Incidence of Chronic Diseases) combines 35 Spanish population cohorts to investigate the clinical, environmental, genetic, and omics determinants of cardiovascular disease in the Southern European population. It aims to conduct the largest genome-wide association study to date on cardiovascular disease in this population, improve predictions of cardiovascular incidence using genomic and clinical data, and identify subgroups that would benefit most from targeted pharmacological and lifestyle interventions. CORDELIA includes 196,632 individuals (ages 18–84, 54% female, 96% born in Spain, 20% with higher education, recruited from 1989 to 2020, with follow-up periods ranging from 5 to 30 years), with DNA samples available for 117,342 participants (60%). Of the participants, 24% were current smokers, 43% hypertensive, 11% diabetic, 15% medicated with lipid-lowering drugs, 44% overweight, and 27% obese. If not already available, genotyping is being performed using the Axiom™ Spain Biobank array (~ 750,000 variants, including 115,000 specific and 50,000 rare functional variants from the Spanish population). The cohort also includes incident events (coronary heart disease, stroke, heart failure, peripheral artery disease, hypertension, diabetes); date and cause of death; and harmonized data on risk factors (body mass index, waist circumference, lipid profile, blood pressure, glucose, creatinine), lifestyle (smoking, physical activity, diet, alcohol), and socioeconomic status. 99,019 participants (50%) also provide plasma samples. CORDELIA will significantly contribute to understanding the complex interplay of risk factors contributing to cardiovascular disease and advance the fields of precision medicine and public health in Southern European individuals.