Medical-administrative databases are an important source of big data to assess the epidemiology of diseases and interventions, compare drugs, and investigate rare adverse events. We describe the French national health insurance system databases and the Epidemiology and Safety (EPISAFE) collaboration program in ophthalmology and illustrate the paper with recent studies that used the databases to investigate cataract surgery. The Système national d'information inter-régime de l'assurance maladie (SNIIR-AM) is one of the largest databases of medical and administrative data for a general population, covering nearly 65 million people. The SNIIR-AM database links data for all outpatient-reimbursed health expenditures, hospitalization in all 1,546 French private or public healthcare facilities, and date of death. The use of this database provides information at the scale of the entire country, allowing measurement of the impact of changes in practices and new guidelines. Between 2009 and 2012, a total of 2,717,203 eyes in 1,817,865 patients underwent cataract surgery in France, and the incidence of cataract surgery increased from 9.86 to 11.08/1,000 person-years. The 4-year cumulative risk of retinal detachment was 0.99%, and patients <60 years of age were at higher risk of retinal detachment. The incidence of pseudophakic cystoid macular edema was 0.95%. From 2005 to 2014, from data including more than 6 million procedures, the incidence of endophthalmitis after cataract surgery decreased from 0.15 to 0.05%. The EPISAFE collaboration program encompasses the key issues facing ophthalmology, including public health and public policy concerning disease incidence and prevalence, safety and adverse event monitoring, and clinical guidelines.