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Key Points Question Are antibiotics appropriately prescribed for infection prophylaxis before dental procedures? Findings In this cohort study of 91 438 patients who received antibiotic prophylaxis for 168 420 dental visits from 2011 to 2015, a total of 90.7% of dental visits had manipulation of the gingiva or tooth periapex, but only 20.9% of patients had a cardiac condition at the highest risk of adverse outcome from infective endocarditis. Therefore, 80.9% of antibiotic prophylaxis prescriptions were discordant with guidelines. Meaning Most antibiotics prescribed for infection prophylaxis before dental procedures are unnecessary., This cohort study assesses the appropriateness of antibiotic prophylaxis prescriptions for infection prophylaxis before dental procedures using Truven, a US national integrated health claims database., Importance Antibiotics are recommended before certain dental procedures in patients with select comorbidities to prevent serious distant site infections. Objective To assess the appropriateness of antibiotic prophylaxis before dental procedures using Truven, a national integrated health claims database. Design, Setting, and Participants Retrospective cohort study. Dental visits from 2011 to 2015 were linked to medical and prescription claims from 2009 to 2015. The dates of analysis were August 2018 to January 2019. Participants were US patients with commercial dental insurance without a hospitalization or extraoral infection 14 days before antibiotic prophylaxis (defined as a prescription with ≤2 days’ supply dispensed within 7 days before a dental visit). Exposures Presence or absence of cardiac diagnoses and dental procedures that manipulated the gingiva or tooth periapex. Main Outcomes and Measures Appropriate antibiotic prophylaxis was defined as a prescription dispensed before a dental visit with a procedure that manipulated the gingiva or tooth periapex in patients with an appropriate cardiac diagnosis. To assess associations between patient or dental visit characteristics and appropriate antibiotic prophylaxis, multivariable logistic regression was used. A priori hypothesis tests were performed with an α level of .05. Results From 2011 to 2015, antibiotic prophylaxis was prescribed for 168 420 dental visits for 91 438 patients (median age, 63 years; interquartile range, 55-72 years; 57.2% female). Overall, these 168 420 dental visits were associated with 287 029 dental procedure codes (range, 1-14 per visit). Most dental visits were classified as diagnostic (70.2%) and/or preventive (58.8%). In 90.7% of dental visits, a procedure was performed that would necessitate antibiotic prophylaxis in high-risk cardiac patients. Prevalent comorbidities include prosthetic joint devices (42.5%) and cardiac conditions at the highest risk of adverse outcome from infective endocarditis (20.9%). Per guidelines, 80.9% of antibiotic prophylaxis prescriptions before dental visits were unnecessary. Clindamycin was more likely to be unnecessary relative to amoxicillin (odds ratio [OR], 1.10; 95% CI, 1.05-1.15). Prosthetic joint devices (OR, 2.31; 95% CI, 2.22-2.41), tooth implant procedures (OR, 1.66; 95% CI, 1.45-1.89), female sex (OR, 1.21; 95% CI, 1.17-1.25), and visits occurring in the western United States (OR, 1.15; 95% CI, 1.06-1.25) were associated with unnecessary antibiotic prophylaxis. Conclusion and Relevance More than 80% of antibiotics prescribed for infection prophylaxis before dental visits were unnecessary. Implementation of antimicrobial stewardship in dental practices is an opportunity to improve antibiotic prescribing for infection prophylaxis.