PURPOSE: Understanding medical student empathy is important to future patient care; however, the definition and development of clinical empathy remain unclear. The authors sought to examine the underlying constructs of two of the most widely used self-report instruments-Davis's Interpersonal Reactivity Index (IRI) and the Jefferson Scale of Empathy version for medical students (JSE-S)-plus, the distinctions and associations between these instruments. METHOD: Between 2007 and 2014, the authors administered the IRI and JSE-S in three separate studies in five countries, (Brazil, Ireland, New Zealand, Portugal, and the United Kingdom). They collected data from 3,069 undergraduate medical students and performed exploratory factor analyses, correlation analyses, and multiple linear regression analyses. RESULTS: Exploratory factor analysis yielded identical results in each country, confirming the subscale structures of each instrument. Results of correlation analyses indicated significant but weak correlations (r = 0.313) between the total IRI and JSE-S scores. All intercorrelations of IRI and JSE-S subscale scores were statistically significant but weak (range r = -0.040 to 0.306). Multiple linear regression models revealed that the IRI subscales were weak predictors of all JSE-S subscale and total scores. The IRI subscales explained between 9.0% and 15.3% of variance for JSE-S subscales and 19.5% for JSE-S total score. CONCLUSIONS: The IRI and JSE-S are only weakly related, suggesting that they may measure different constructs. To better understand this distinction, more studies using both instruments and involving students at different stages in their medical education, as well as more longitudinal and qualitative studies, are needed.