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Objectives. To evaluate the impact of the Southern Public Health Regions’ (Regions IV and IV) Collaborative Improvement and Innovation Network (CoIIN) to Reduce Infant Mortality, supported by the US Health Resources and Services Administration. Methods. We examined pre–post change (2011–2014) for CoIIN strategies with available outcome data from vital records (early elective delivery, smoking) and the Pregnancy Risk Assessment Monitoring System (safe sleep) as well as preterm birth and infant mortality for Regions IV and VI relative to all other regions. Results. For most outcomes, CoIIN improvements were greater in Regions IV and VI than in other regions. For example, early elective delivery decreased by 22% versus 14% in other regions, smoking cessation during pregnancy increased by 7% versus 2%, and back sleep position increased by 5%versus 2%. Preterm birth decreased by 4%, twice that observed in other regions, but infant mortality reductions did not differ significantly. Conclusions. The CoIIN approach to public health improvement shows promise in accelerating progress in intermediate outcomes and preterm birth. Impact on infant mortality may require additional strategies and sustained efforts. [ABSTRACT FROM AUTHOR]