Background: Determining the histology of borderline enlarged nodes in clinical stage I (CSI) or post-chemotherapy residual disease (PCRD) patients (pts) with germ cell tumor (GCT) is challenging, especially when classic tumor markers are negative. Currently, accurate assessment requires clinical follow-up with imaging to establish patterns of growth or pathological confirmation. A blood-based approach to reliably identify patients with non teratoma viable GCT (NTVGCT) would be valuable. Methods: miR-371a-3p (miR371) extracted from plasma of pts with GCT was analyzed by RT-PCR and relative expression calculated by the 2-ΔΔCt method with appropriate negative and positive controls. The sensitivity and specificity of miR371 were calculated correlating miR371 expression to the presence of relapsed/residual NTVGCT. Results: 74 samples were analyzed in 56 patients: 24 CSI; 32 metastatic, of whom 21 had PCRD. Among CSI patients, 8 relapses occurred and miR371 was positive in 6/8 relapses. Among the CSI patients that did not relapse, 7 had borderline enlarged nodes but negative miR371. For the metastatic pts, miR371 was positive in 16/18 pts pre-chemotherapy and became negative in all post-chemotherapy. 3 miR371 negative pts (1 CSI and 2 metastatic) had pathologically confirmed primary teratoma. miR371 was negative in all the pts with PCRD (n = 21) and no residual NTVGCT was detected in those pts by either pathology (n = 13) or clinical follow-up (n = 8). Sensitivity and specificity were 93.3% and 100%, respectively across the entire cohort of samples in detecting the presence of relapse or residual NTVGCT. Both internal and external validation studies have been performed with excellent concordance. Conclusions: Detectable plasma levels of miR371 have excellent correlation with the presence of NTVGCT. More rational selection of adjuvant therapy in CSI, reduction in imaging and more precise post-chemotherapy evaluations are among the more obvious settings in which biomarker-based decision making can improve GCT management. These and other data informed the development of two large US/Canadian intergroup studies to define the role of miRNA clusters in management of GCT.