Background: The shortage of nursing professionals is of growing concern. The causes of this include the demanding physical and mental workload, leading to a dropout of nurses that may start during their education. However, it is unclear to what extent nursing students already perceive a physical and mental workload leading to health problems during their nursing education and placement, and to what extent these health problems cause students to dropout from nursing education. Very few prospective cohort studies have investigated protective and risk factors in relation to dropout and retention among nursing students. Methods: Three cohorts of third-year nursing students will be followed for 2.5 years. Students will be enrolled from the Bachelor of Nursing program of the Rotterdam University of Applied Sciences. At baseline, students will receive a self-administered questionnaire. Primary outcome is dropout from nursing education and dropout from the nursing profession. Data on dropout from nursing education will be retrieved from the student administration on a yearly basis. Dropout from the nursing profession will be measured one year after graduation, using the self-reported questionnaire. Secondary outcomes are presenteeism and sick leave (during internship/work). In addition to student characteristics, the questionnaire asks about physical and mental internship/work characteristics, personal and behavioral factors, and experienced physical and mental burden. Main aims of this study are to determine: 1) the prevalence and incidence rates of dropout, 2) the protective and risk factors, and early indicators of dropout, and 3) the interaction between these factors and the indicators. Discussion: Data analysis of a large, prospective cohort study with regard to determinants of dropout and retention of nursing students and newly graduated nurses is in progress. Findings emerging from this study can be used to develop a predictive model to identify the first indicators of dropout from nursing education and nursing profession, for which targeted interventions can be deployed.