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Medical students have reported high prevalence of mental health difficulties and burnout. However, there are limited investigations examining the association between resilience and these difficulties. We investigated: (1) depression, anxiety, personal and professional burnout, and comorbidity; (2) demographic and education characteristics associated with these outcomes; (3) the association between resilience and these outcomes; and (4) whether these results were attributable to sampling bias. Participants were n = 521 medical students from RCSI University of Medicine and Health Sciences. Outcomes were measured using validated scales. We report descriptive statistics, and risk factors for the difficulties were investigated using generalized linear modelling. One-in-three students reported incidence of depression or anxiety (24.5% co-morbidity). 8.9% of students reported all four difficulties. Difficulties were more common in female students and those in middle years of the programme. Resilience was negatively correlated with all outcomes and stable across demographic and educational variables. Weighting the data for sampling bias did not affect these results. Our results emphasise the high incidence of depression, anxiety, burnout, and comorbidity in students. We advocate for further investigation into the role of resilience as a modifiable factor that may ameliorate the incidence of depression, anxiety, and burnout in medical students. [ABSTRACT FROM AUTHOR]