Objectives: To describe current syndromic surveillance system response protocols in health departments from 8 diverse states in the United States and to develop a framework for health departments to use as a guide in initial design and/or enhancement of response protocols.

Methods: Case study design that incorporated in-depth interviews with health department staff, textual analysis of response plans, and a Delphi survey of syndromic surveillance response experts.

Results: All 8 states and 30 of the 33 eligible health departments agreed to participate (91% response rate). Fewer than half (48%) of surveyed health departments had a written response protocol, and health departments reported conducting in-depth investigations on fewer than 15% of syndromic surveillance alerts. A convened panel of experts identified 32 essential elements for inclusion in public health protocols for response to syndromic surveillance system alerts.

Conclusions: Because of the lack of guidance, limited resources for development of response protocols, and few examples of syndromic surveillance detecting previously unknown events of public health significance, health departments have not prioritized the development and refinement of response protocols. Systems alone, however, are not effective without an organized public health response. The framework proposed here can guide health departments in creating protocols that will be standardized, tested, and relevant given their goals with such systems. (Disaster Med Public Health Preparedness. 2009;3(Suppl 1):S29–S36)