Introduction: This article reports on the feasibility of conducting a large-scale endodontic prospective cohort study in The National Dental Practice-Based Research Network. This study was designed to measure pain and burden associated with initial orthograde root canal therapy (RCT) and to explore potential prognostic factors for pain outcomes. The main objectives of this first report in a series are to describe the project's feasibility and methods and the demographics of the sample obtained. Methods: Sixty-two dentist practitioner-investigators (ie, 46 generalists and 16 endodontists) in 5 geographic areas were certified within the network and trained regarding the standardized study protocol. Enrollment and baseline data collection occurred over 6 months with postobturation follow-up for another 6 months. Patients and dentists completed questionnaires before and immediately after treatment visits. Patients also completed questionnaires at 1 week, 3 months, and 6 months after obturation. Results: Enrollment exceeded target expectations, with 708 eligible patient-participants. Questionnaire return rates were good, ranging between 90% and 100%. Patient demographics were typical of persons who receive RCT in the United States (ie, mean age = 48 years [standard deviation = 13 years], with most being female [59%], college educated [81%], white non-Hispanic [86%], and having dental insurance [81%]). The tooth types being treated were also typical (ie, 61% molars, 28% premolars, and 11% anteriors, with maxillary teeth being predominant [59%]). Conclusions: This study shows the feasibility of conducting large-scale endodontic prospective cohort studies in the network. Patients were rapidly recruited with high levels of compliance in data collection. © 2012 American Association of Endodontists.