Objective To evaluate the effect of state continuing medical education (CME) requirements on physician clinical knowledge. Data Sources Secondary data for 19,563 general internists who took the Internal Medicine Maintenance of Certification (MOC) examination between 2006 and 2013. Study Design We took advantage of a natural experiment resulting from variations in CME requirements across states over time and applied a difference‐in‐differences methodology to measure associations between changes in CME requirements and physician clinical knowledge. We measured changes in clinical knowledge by comparing initial and MOC examination performance 10 years apart. We constructed difference‐in‐differences estimates by regressing examination performance changes against physician demographics, county and year fixed effects, trend–state indicators, and state CME change indicators. Data Collection Physician data were compiled by the American Board of Internal Medicine. State CME policies were compiled from American Medical Association reports. Principal Findings More rigorous CME credit‐hour requirements (mostly implementing a new requirement) were associated with an increase in examination performance equivalent to a shift in examination score from the 50th to 54th percentile. Conclusions Among physicians required to engage in a summative assessment of their clinical knowledge, CME requirements were associated with an improvement in physician clinical knowledge.