OBJECTIVES:  Although a great deal of real-world physician-patient interaction occurs in small practice settings, not a great deal of real-world research has been performed in these settings. Use of EMR systems facilitates outreach to small practice settings—the objective of this study was to assess interest in participating in real-world research among physicians in these settings. METHODS:  We fielded a 15-item survey to physicians from small practice settings, with items devoted to professional characteristics, interests in particular research methodologies and therapeutic areas, as well as motivations to get involved in research and concerns that might limit involvement. Likert scales ranging from 1 (“not at all”) to 7 (“extremely”) were used in all ratings. Physicians from small practice settings across all fifty states were accessed through their EMR system. RESULTS:  A total of 264 physicians completed the survey, of whom 73.4% were sole practitioners and 87.9% in a 1-2 physician practice. Approximately three-quarters (72.3%) were male and on average they were in practice for two decades (21.6 years); fewer than one-half (46.2%) had ever functioned as a clinical investigator. Highest levels of interest were expressed in physician and patient surveys (4.57 and 4.02 average ratings) and phase IV real-world clinical trials (4.17), and lowest interest levels in phase II-III trials (3.41). Preferences for research in specific therapeutic areas did not differ markedly (3.40-3.95), except for oncology (2.60). Highest ranking motivations for participating in research were to help their patients (5.63) and advance science/medicine (4.82). Highest ranking concerns included devoting time to research and allowing data collection instruments into the EMR (both at 4.27). Three in five physicians (60.5%) indicated interest in being contacted for future research projects. CONCLUSIONS:  Physicians in small practice settings are interested in participating in real-world research. EMR systems can be used to access these physicians and, by extension, the patients they treat.