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**Objectives:** Regulatory bodies, health technology assessment agencies, payers, physicians, and other decision-makers increasingly recognize the importance of real-world evidence (RWE) to provide important and relevant insights on treatment patterns, burden/cost of illness, product safety, and long-term and comparative effectiveness. However, RWE generation requires a careful approach to ensure rigorous analysis and interpretation. There are limited examples of comprehensive methodology for the generation of RWE on patients who have undergone neuromodulation for drug-resistant epilepsy (DRE). This is likely due, at least in part, to the many challenges inherent in using real-world data to define DRE, neuromodulation (including type implanted), and related outcomes of interest. We sought to provide recommendations to enable generation of robust RWE that can increase knowledge of “real-world” patients with DRE and help inform the difficult decisions regarding treatment choices and reimbursement for this particularly vulnerable population. **Methods:** We drew upon our collective decades of experience in RWE generation and relevant disciplines (epidemiology, health economics, and biostatistics) to describe challenges inherent to this therapeutic area and to provide potential solutions thereto within healthcare claims databases. Several examples were provided from our experiences in DRE to further illustrate our recommendations for generation of robust RWE in this therapeutic area. **Results:** Our recommendations focus on considerations for the selection of an appropriate data source, development of a study timeline, exposure allotment (specifically, neuromodulation implantation for patients with DRE), and ascertainment of relevant outcomes. **Conclusions:** The need for RWE to inform healthcare decisions has never been greater and continues to grow in importance to regulators, payers, physicians, and other key stakeholders. However, as real-world data sources used to generate RWE are typically generated for reasons other than research, rigorous methodology is required to minimize bias and fully unlock their value.