Performance-based grants management is a strategy used by public agencies to improve performance and strengthen accountability by connecting annual award amounts to performance information. This study evaluates the impacts of a performance-based grants management process implemented by the U.S. Centers for Disease Control and Prevention to strengthen the effectiveness of its National Breast and Cervical Cancer Early Detection Program. The study uses panel data and interrupted time-series analysis over 10 years for 51 grantees. Results show partial and conditional effectiveness of the performance-based grants management process in strengthening performance. In particular, the implementation of the performance-based grants management system consistently improved the performance of those grantees for whom the targets were challenging. While prior research has found, in some cases, evidence of a positive impact of performance management practices in improving programs delivered directly by public organizations at the local level, this study examines the performance management–performance relationship in a more challenging context of a federal grants program delivered through a highly decentralized system.