Background: Although both seminomatous (Sem) and nonseminomatous (NS) TGCT have a favorable response to platinum-based chemotherapy (CT), a small proportion of them are chemorefractory. Therapeutic options for these patients (pts) are limited, and relevant therapeutic targets are lacking. Methods: The database of Foundation Medicine Inc. was searched, integrated with relevant clinical data. Archival tissues from 108 CT-treated and relapsed TGCT pts (22 Sem and 86 NS) underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations (mut) per megabase (Mb) and microsatellite instability (MSI) was determined on 114 loci. Results: Sem pts were older than NS (p = 0.007). All pts had failed at least 1 CT regimen for metastatic disease. The mean GA/tumor frequency was 4.1 mut/tumor for NS and 3.1 for Sem (p = 0.08). KRAS alterations (mainly amplifications) were the most frequent GA (47% and 36% in Sem and NS). TP53, CCND2 and FGF6/23 GA frequencies were similar in both Sem and NS. GA in KIT (21% vs 2%), PIK3CA/MTOR (10% vs 0%), PTEN (5% vs 0%) and BRCA2 (5% vs 0%) were more frequent in Sem than NS whereas BRAF (2%) and ERBB2 (1%) GA were found in NS only. Among pts with MTOR alterations, one Sem was treated based on genomic profiling and had an exceptional response to everolimus, after CT and immunotherapy (IT) failure. MSI-High status was not identified in Sem cases and was found only in 2% of NS. The median TMB for the Sem cases was 2.5 mut/Mb and for NS was 2.7 mut/Mb. TMB levels of ≥10 mut/Mb were not encountered in Sem. Higher levels of TMB were more frequent in NS with 5% of NS having ≥10 mut/B and 1% ≥20 mut/Mb. Conclusions: Clinical trials in molecularily-selected pts are warranted for refractory TGCT, particularly the high frequency of KRAS amplification may portend activity of MEK inhibitors. Overall, the GA found in refractory Sem and NS differ significantly. Sem features lower GA frequency with slightly higher potential for targeted therapies in KIT and PI3K/MTOR pathways. Based on rare high TMB and MSI-High status, IT may be of benefit in a small subset of NS.