Introduction: Although research in continuing medical education (CME) demonstrates positive outcomes of on-line CME programs, the effectiveness of and learners' satisfaction with interpersonal interaction in on-line CME are lower. Defined as faculty-learner or learner-learner interpersonal interaction, this study explores physicians' perceptions of and experiences in interactive on-line CME and factors influencing these. Methods: Focus groups and interviews were undertaken by three Canadian universities. Using purposive sampling, we recruited physicians based on their experiences with interactive on-line CME. Content analysis was applied first, followed by a comparative analysis to confirm themes and findings. Results: Physicians based their perceptions of interactive on-line CME by comparing it with what they know best, face-to-face CME. Although perceptions about access and technical competency remained important, two other themes emerged. The first was the capacity of on-line CME to meet individual learning preferences, which, in turn, was influenced by the quality of the program, the degree of self-pacing or self-direction, opportunity for reflection, and educational design. The second was the quality and quantity of interpersonal interaction, which was shaped by perceptions of social comfort, the educational value of interactions, and the role of the facilitator: Prior experience with on-line CME moderated perceptions. Discussion: The extent that on-line CME programs reflected characteristics of high-quality CME and individual learning preferences appeared to shape perceptions about it. It is important to incorporate the characteristics of effective CME into the design and implementation of interactive on-line programs, considering diverse learning preferences, providing faculty development for on-line facilitators, and grounding this work in learning theory.