Novice medical students usually hold initial conceptions concerning medical domains, such as the cardiovascular system, which may contradict scientific explanations and thus hinder learning. The purpose of this study was to investigate which kinds of biomedical representations medical students constructed of the central cardiovascular system in their first and second years of study, and how the quality of these representations was related to the students' success in clinical reasoning. Data for 119 medical students were collected in three phases: in the first year of study before and after a cardiovascular course and a follow-up in the second year of study. Biomedical and clinical assignments were utilised. The study revealed that students had a substantial number of different misconceptions, and they decreased only slightly over the period of instruction. Those students who had misconceptions concerning biomedical knowledge also performed poorly in clinical reasoning. Furthermore, those students whose clinical reasoning was excellent had improved their biomedical knowledge between the first and second year remarkably more than students with poorer clinical reasoning. Hence, biomedical understanding seems to act as a mediator in clinical reasoning among novice students. We suggest that domain-specific pedagogical training, which would help medical educators become aware of students' typical misconceptions concerning biomedical knowledge and the role of this knowledge in clinical reasoning, should be carried out to improve medical education.