--- - |2+ Abstract Objective Decisions to limit life‐prolonging treatment (DLT) are often accompanied by psychological and ethical difficulties. The aim of the study is to investigate prevalence and intensity of moral distress (MD) as well as potential causes experienced by oncology physicians and nurses in DLT situations. Methods This prospective study at a German university hospital included n = 100 advanced cancer inpatients with DLT. We surveyed their respective physicians and nurses to assess MD in DLT using an adapted distress thermometer and an open‐ended question to specify reasons of MD. We also collected data on the decision‐making process from the perspective of the clinicians. Results Physicians report MD in 67% (n = 51) and nurses in 74% (n = 67) of the cases. The MD level in nurses (mean 2.3; SD 2.3) is significantly higher (P = .005) than in physicians (mean 1.5; SD 1.4). Uncertainties concerning ethical aspects in DLT in a patient case are associated with MD in both physicians (P = .024) and nurses (P = .004). Involvement of nurses in DLT is the strongest predictor (P = .000) for MD as indicated by physicians. Nurses experience MD especially, if the patient has a low quality of life (P = .001). Conclusions Moral distress is experienced by both oncologists and nurses in DLT. Nurses report higher MD intensity compared with physicians although the ultimate responsibility for DLT lies with the physicians. Support for the challenging decisions may be provided through the implementation of an ethical guideline and enhanced interprofessional communication. - Psycho-Oncology, EarlyView.