The Readiness Evaluation and Discharge Interventions (READI) study was a multisite randomized clinical trial that used a pragmatic comparative effectiveness design, with randomization at the nursing unit level, to determine the optimal protocol for implementing a structured discharge readiness assessment as a standard practice for hospital discharge. Three variations of a protocol for discharge readiness were compared with baseline and concurrent control conditions, implementing in sequence nurse assessment, patient + nurse assessment, and required action for low readiness scores. Implementation evaluation contributed to understanding the factors that influenced the successful completion of the study and to interpreting the quantitative findings. Challenges included recruitment and engagement of the 34 clinical sites, sustaining the study over a long data collection period, variation in site principal investigator experience with research, communication with sites, institutional review board approval processes, acquisition of data from hospital information systems and data management, and the complexity of analysis. Despite the many complexities and challenges in multisite pragmatic clinical trials, the major benefit is in generating actionable results that can be widely and immediately used in practice.