Purpose: To present the design and system architecture of the National Radiation Oncology Registry (NROR) to electronically collect aggregated data on cancer patients treated with radiotherapy with the goal of evaluating comparative effectiveness of competing radiotherapy treatments, outcomes, “patterns of care”, gaps in quality, safety, and cost. Methods: The design requirements include a secure automatic upload and archival of anonymized patient data, a web‐based upload/download tool for reviewing the collected data in a distributed database environment. The system design and architecture utilizes Web‐based technology and current available commercial products to automatically abstract dosimetric parameters from the treatment planning systems and outcome parameters from clinician reported outcome (CRO) portal, patient reported outcome (PRO) portal, and radiotherapy electronic medical record (RT‐EMR) systems. A centralized NROR Server would contain interfaces, templates and data dictionary, allowing integration of all collected patient data into a centralized data base and would provide a web ‐based tool to manage, review and analyze these data for outcome and competitive effectiveness research (OCER). Results: The design and system architecture is ready for implementation. A pilot registry of prostate cancer patients treated with different modalities of radiation treatments is planned to test the electronic infrastructure for registry data collection. The system will be initially deployed at a limited number of volunteer institutions (approximately 20) to test the concepts and sustainability of the NROR. These institutions will be selected in such a way that they represent a population‐based sample for OCER. Conclusions: The establishment of the National Radiation Oncology Registry will be of great benefit to treating radiation oncologists and other care providers, payors, vendors, policy‐makers and most importantly cancer patients by capturing reliable information on population based treatment delivery and health outcomes.