Objective Previous studies have suggested that Medical students' empathy declines during medical school, especially during clinical studies. The aim of this study was to examine whether humanities curriculum and admission system affect empathy changes during the first clinical year in medical school. Methods In this prospective longitudinal study, 262 students were assessed during the fourth-year of medical school. Empathy was assessed before and at 4th-year-end, using the Jefferson Scale of Physician Empathy-Student Version (JSPE-S). The study included three cohorts, differing in humanities curriculum [limited Medical Humanities (MH (lim) ) vs. extended Medical Humanities (MH (ext) )], and in admission system [Personal Interview (PI) vs. multiple mini interviews (MMI)]. Results Among women, but not among men, MH (ext) as compared to MH (lim) was associated with significantly higher JSPE-S at the beginning (118.47±11.43 vs. 110.36±9 .97, p <0.001), and end of 4th-year (117.97±12.86 vs. 111.49±14.42, p <0.001), (p=0.009). Admission system was not associated with JSPE-S at the beginning or at the end of the 4th year. Conclusion Among women, extended MH program had a positive effect on empathy at the beginning of the first clinical year, as compared to the limited program. This effect persisted through that year. However, in men MH program did not affect empathy. Adopting MMI-based admission system had no measurable effect on students’ empathy. Extensive educational program can enhance and sustain empathy in medical students during the first clinical year following the program. Gender differences in response to medical humanities programs requires further study.