Most malignant ovarian germ cell tumors (MOGTCs) have a very good prognosis and can be cured by chemotherapy, with yolk sac tumors (OYSTs) having the worse prognosis among MOGCTs. These tumors are rare and can benefit in the next future from specific therapeutic strategies after failure of platinum-based first-line and salvage regimens. In collaboration with EORTC SPECTA, we have developed a project to explore the molecular characteristics of OYST. The pilot part of the project was performed using retrospective samples and ten OYST patients including relapsed and disease free patients. The molecular analysis was performed using FoundationOne CDx. For each patient, the following variables are described in the molecular report provided by FMI (Fondation Medicine Incorporation): alteration type (SNV, deletion), actionable gene alteration, therapies approved in EU (patient's tumor type and other tumor types), tumor mutational burden (TMB) and microsatellite instability (MSI) status. A total of 10 patients with OYST diagnosed between 2007 and 2017 were analyzed. Four patients (40%) had a molecular alteration, according to the FMI test. A subset of three patients (33.3% of all patient) harbored targetable (KRAS, KIT, ARID1A) oncogenic mutations. Two patients at relapse harbored a targetable mutation. In this retrospective study, we were able to identify clinically relevant molecular alterations for all relapsed patients with molecular analysis. Dedicated studies are needed to demonstrate if they could benefit from specific therapeutic strategies after failure of platinum-based first-line and salvage regimens and if the presence of a molecular alteration could be linked to patients’ outcome.