Background: Patient self-management interventions for smoking cessation are effective but underused. Health care providers do not routinely refer smokers to these interventions. Objective: The objective of our study was to uncover barriers and facilitators to the use of an e-referral system that will be evaluated in a community-based randomized trial. The e-referral system will allow providers to refer smokers to an online smoking intervention during routine clinical care. Methods: We devised a four-step development and pilot testing process: (1) system conceptualization using Delphi to identify key functionalities that would overcome barriers in provider referrals for smoking cessation, (2) Web system programming using agile software development and best programming practices with usability refinement using think-aloud testing, (3) implementation planning using the nominal group technique for the effective integration of the system into the workflow of practices, and (4) pilot testing to identify practice recruitment and system-use barriers in real-world settings. Results: Our Delphi process (step 1) conceptualized three key e-referral functions: (1) Refer Your Smokers, allowing providers to e-refer patients at the point of care by entering their emails directly into the system, (2) practice reports, providing feedback regarding referrals and impact of smoking-cessation counseling, and (3) secure messaging, facilitating provider-patient communication. Usability testing (step 2) suggested the system was easy to use, but implementation planning (step 3) suggested several important approaches to encourage use (eg, proactive email cues to encourage practices to participate). Pilot testing (step 4) in 5 practices had limited success, with only 2 patients referred; we uncovered important recruitment and system-use barriers (eg, lack of study champion, training, and motivation, registration difficulties, and forgetting to refer). Conclusions: Implementing a system to be used in a clinical setting is complex, as several issues can affect system use. In our ongoing large randomized trial, preliminary analysis with the first 50 practices using the system for 3 months demonstrated that our rigorous preimplementation evaluation helped us successfully identify and overcome these barriers before the main trial. © Rajani S Sadasivam, Kathryn Delaugther, Katie Crenshaw, Heather J Sobko, Jessica H Williams, Heather L Coley, Midge N Ray, Daniel E Ford, Jeroan J Allison, Thomas K Houston.