Background: New data management models are emerging in multi-center clinical studies. We evaluated the incremental costs associated with decentralized vs. centralized models. Methods: We developed clinical research network economic models to evaluate three data management models: centralized, decentralized with local software, and decentralized with shared database. Descriptive information from three clinical research studies served as inputs for these models. Main Outcome Measures: The primary outcome was total data management costs. Secondary outcomes included: data management costs for sites, local data centers, and central coordinating centers. Results: Both decentralized models were more costly than the centralized model for each clinical research study: the decentralized with local software model was the most expensive. Decreasing the number of local data centers and case book pages reduced cost differentials between models. Conclusion: Decentralized vs. centralized data management in multi-center clinical research studies is associated with increases in data management costs.