Background: Studies on the widespread use of complementary and alternative medicine (CAM) demonstrate that CAM users base their treatment decisions on both subjective, experience-based knowledge and medical knowledge. The aim of this study was to explore lay and medical risk perceptions associated with CAM and conventional medicine. Patients and Methods: In this explorative qualitative study, we conducted in-depth interviews with 25 Norwegian CAM users with cancer or multiple sclerosis and 12 doctors. Results: The interviews revealed fundamental differences in risk perceptions influencing treatment decisions and risk communication in a clinical setting. While CAM users considered conventional medicine as potentially risky and related this to experiences of severe adverse effects, CAM was perceived as natural and safe. Doctors' risk perceptions were quite the contrary, mainly because of lack of scientific evidence for CAM as a safe and beneficial treatment option. Conclusion: For the safety of CAM users, such divergent risk perceptions may have far-reaching consequences. CAM users should be taken seriously with their self-perception as decision-makers considering their approaches to experiences, knowledge, and science. An awareness of differing lay and medical risk perceptions associated with CAM and conventional medicine in research, doctor-patient communication, and education of patients and doctors is thus important to optimize patient safety in complex health care systems.