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The substantial interest and investment in health partnerships in the United States is based on the assumption that collaboration is more effective in achieving health and health system goals than efforts carried out by single agents. A clear conceptualization of the mechanism that accounts for the collaborative advantage, and a way to measure it are needed to test this assumption and to strengthen the capacity of partnerships to realize the full potential of collaboration. The mechanism that gives collaboration its unique advantage is synergy. A framework for operationalizing and assessing partnership synergy, and for identifying its likely determinants, can be used to address critical policy, evaluation, and management issues related to collaboration.