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Background: Cross-system interventions can help integrate services across different service delivery systems but require organizations to establish strong collaborative relationships for implementation. Contingency theory suggests that the effectiveness of different collaborative strategies (i.e. specific ways organizations align operations and services) varies by context. This paper describes a study of different strategies for fostering collaboration between child welfare and substance abuse treatment agencies and the conditions under which they are effective for implementation. We also describe the development and piloting of the Collaborating Across Systems for Program Implementation (CASPI) tool-a decision-making guide intended to help researchers and organizational leaders identify and use appropriate collaborative strategies for their context.Methods/design: This multisite longitudinal, mixed methods study, leverages a naturally occurring implementation initiative -- in up to 17 Ohio counties -- to implement Ohio START (Sobriety Treatment and Reducing Trauma). START is a child welfare model that requires strong collaboration with local substance use treatment organizations to promote integrated services. During the first two years, we will identify collaborative strategies associated with improved START implementation (penetration and fidelity) and service delivery outcomes (timeliness), given system, and organizational features. We will conduct a convergent mixed methods study drawing on worker surveys, agency documents, administrative data, formal partner agreements, and group interviews. Data will be integrated and analyzed using Qualitative Comparative Analysis (QCA). To develop the CASPI, an expert panel comprised of implementation experts, and community stakeholders will convene to synthesize our findings and develop contents (including a decision tree). During the final year of the study, we will assess the acceptability, appropriateness, and feasibility of the CASPI in a randomized vignette experiment, and a pilot-test with 3 child welfare agencies that have not yet implemented START.Discussion: Our results will lay the groundwork for a larger controlled trial that will test the CASPI's effectiveness for supporting effective and efficient implementation of cross-system interventions like START. The CASPI is expected to help leaders and researchers select and use collaboration strategies tailored to their context and be applicable in a wide range of settings including rural communities. Our work also advances system-level implementation strategies.Trial Registration: NCT03931005 , Registered April 29, 2019. [ABSTRACT FROM AUTHOR]