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Purpose: The purpose of the current study was to identify and describe strategies available to optimize retention of a high-risk research cohort and assist in the recovery of study participants following participant dropout. Design and Methods: The Maternal Lifestyle Study (MLS), which investigated the effects of prenatal substance exposure (cocaine or opiates) on child outcome, is a prospective longitudinal follow-up study that extended from birth through 15 years of age. Retention strategies to maximize participation and factors that might negatively impact compliance were examined over the course of five follow-up phases. Findings: At the conclusion of the 15-year visits, MLS had successfully maintained compliance at 76%. Retention rates did not differ by exposure group. Conclusions: Maintaining ongoing participation of enrolled study subjects is a critical element of any successful longitudinal study. Strategies that can be used to reengage and maintain participants in longitudinal research include persistence, flexibility with scheduling, home visits, long-distance trips, increased incentives, and development of a computerized tracking system. Establishing rapport with families and ensuring confidentiality contributed to overall participant retention. The use of multiple tracking techniques is essential. Clinical Relevance: Researchers are challenged to maintain participants in longitudinal studies to ensure the integrity of their research. Journal of Nursing Scholarship, 2012; 00:0, 1-7. (c)2012 Sigma Theta Tau International