Importance: On October 1, 2015, the US transitioned to the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) for recording diagnoses, symptoms, and procedures. It is unknown whether this transition was associated with changes in diagnostic category prevalence based on diagnosis classification systems commonly used for payment and quality reporting. Objective: To assess changes in diagnostic category prevalence associated with the ICD-10-CM transition. Design, Setting, and Participants: This interrupted time series analysis and cross-sectional study examined level and trend changes in diagnostic category prevalence associated with the ICD-10-CM transition and clinically reviewed a subset of diagnostic categories with changes of 20% or more. Data included insurance claim diagnoses from the IBM MarketScan Commercial Database from January 1, 2010, to December 31, 2017, for more than 18 million people aged 0 to 64 years with private insurance. Diagnoses were mapped using 3 common diagnostic classification systems: World Health Organization (WHO) disease chapters, Department of Health and Human Services Hierarchical Condition Categories (HHS-HCCs), and Agency for Healthcare Research and Quality Clinical Classification System (AHRQ-CCS). Data were analyzed from December 1, 2018, to January 21, 2020. Exposures: US implementation of ICD-10-CM. Main Outcomes and Measures: Monthly rates of individuals with at least 1 diagnosis in a diagnostic classification category per 10000 eligible members. Results: The analytic sample contained information on 2.1 billion enrollee person-months with 3.4 billion clinically assigned diagnoses; the mean (range) monthly sample size was 22.1 (18.4 to 27.1 ) million individuals. While diagnostic category prevalence changed minimally for WHO disease chapters, the ICD-10-CM transition was associated with level changes of 20% or more among 20 of 127 HHS-HCCs (15.7%) and 46 of 282 AHRQ-CCS categories (16.3%) and with trend changes of 20% or more among 12 of 127 of HHS-HCCs (9.4%) and 27 of 282 of AHRQ-CCS categories (9.6%). For HHS-HCCs, monthly rates of individuals with any acute myocardial infarction diagnosis increased 131.5% (95% CI, 124.1% to 138.8%), primarily because HHS added non-ST-segment-elevation myocardial infarction diagnoses to this category. The HHS-HCC for diabetes with chronic complications increased by 92.4% (95% CI, 84.2% to 100.5%), primarily from including new diabetes-related hypoglycemia and hyperglycemia codes, and the rate for completed pregnancy with complications decreased by 54.5% (95% CI, -58.7% to -50.2%) partly due to removing vaginal birth after cesarean delivery as a complication. Conclusions and Relevance: These findings suggest that the ICD-10-CM transition was associated with large prevalence changes for many diagnostic categories. Diagnostic classification systems developed using ICD-9-CM may need to be refined using ICD-10-CM data to avoid unintended consequences for disease surveillance, performance assessment, and risk-adjusted payments.