Objective Several reports have shown that despite the informed consent process, enrolled patients misunderstand the modalities and goals of randomized clinical trials (RCTs). We believe that this may be linked to a priori misconceptions in the main population. The purpose of this study is to compare the knowledge about cancer RCTs in enrolled participants (cases) versus patients treated under cancer standard care who have never taken part in RCTs (controls). Methods We submitted a validated questionnaire (ICEC-R) to both populations to explore their knowledge about RCTs. A total of 75 cases and 107 controls were included. Results Globally, the cases' knowledge was significantly better, especially about (i) the randomization process, (ii) the uncertain potential benefits, and (iii) the right to withdraw consent. Both populations presented the lowest scores for items exploring the randomization process and uncertain treatment benefits. Conclusion Enrolled patients' comprehension of the goals and means of RCTs is actually better than controls'. Nevertheless, additional efforts should be made to enhance information about clinical research to patients as well as to the main population. Practice Implications Having better knowledge about patients' difficulties in understanding RCTs would allow physicians to adjust the information they give and then to enhance patients' well-being.