Background Existing research has suggested that self-reported empathy in medical students is moderated by personality traits and diverse demographic and educational factors including age, gender, nationality, career aspirations, as well as year of curriculum. It is unclear how empathy, personality, and background factors might impact on students’ attitudes towards professionalism in medicine. Methods A cross-sectional questionnaire-based study was conducted in first and final year medical students at an Irish medical school. The following instruments were administered: (a) Jefferson Scale of Empathy; (b) NEO Five-Factor Inventory (NEO-FFI-3); (c) Attitudes towards Professionalism Scale. Demographic and educational variables were also measured. Descriptive and correlational analysis was conducted to examine the association between empathy, personality, professionalism-related attitudes and additional measures. Regression analysis was used to examine determinants of attitudes towards professional behaviour. Results Both selected NEO-FFI personality traits and empathy were independently associated with distinct categories of professional behaviour. Specifically, Openness to Experience was associated with higher empathy scores, and higher ‘Social responsibility’. Extraversion was linked with higher scores on the “Personal characteristics” and “Interactions with team” categories, while Conscientiousness was also positively associated with “Personal characteristics”. In agreement with previous studies, the personality traits most associated empathy were Agreeableness and Openness to Experience. Empathy did not vary according to programme year or career specialty preference. Conclusions This study is the first to show that empathy and personality factors may act as determinants of students’ attitudes towards medical professionalism in a manner which is dependent upon category of professional behaviour.