Based on experiences implementing the Reaching Every District using Quality Improvement (RED-QI) approach in Uganda and Ethiopia, this guide provides information mainly targeted at national and sub-national level immunization program staff on the operational details and best practices for planning, implementing, and monitoring and evaluating RED-QI. It also includes the key tools used in the approach, as well as other quality improvement tools and practices that can be adapted for local use and to the needs and scope of immunization programs.