National surveillance provides important information about Lyme disease (LD) but is subject to underreporting and variations in practice. Information is limited about the national epidemiology of LD from other sources. Retrospective analysis of a nationwide health insurance claims database identified patients from 2005-2010 with clinician-diagnosed LD using International Classification of Diseases, Ninth Revision, Clinical Modification, codes and antimicrobial drug prescriptions. Of 103,647,966 person-years, 985 inpatient admissions and 44,445 outpatient LD diagnoses were identified. Epidemiologic patterns were similar to US surveillance data overall. Outpatient incidence was highest among boys 5-9 years of age and persons of both sexes 60-64 years of age. On the basis of extrapolation to the US population and application of correction factors for coding, we estimate that annual incidence is 106.6 cases/100,000 persons and that ≈329,000 (95% credible interval 296,000-376,000) LD cases occur annually. LD is a major US public health problem that causes substantial use of health care resources.