Background: Cisplatin resistance occurs in up to 30% of patients with advanced germ cell tumors (GCTs). Despite effective salvage treatment regimen, there is a 50% risk of cancer-specific death. Previously, we identified molecular features, including TP53 mutations and MDM2 amplification, associated with cisplatin resistance (Bagrodia, 2016). Herein, we evaluate the genomic and transcriptomic landscapes of chemotherapy naïve vs post-chemotherapy GCT’s to uncover genetic factors that might drive cisplatin resistance. Methods: GCTs (N = 138) were tested at Caris Life Sciences (Phoenix, AZ) with next-generation sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). Prevalence was calculated for pathogenic SNVs/indels and copy number amplifications (CNA≥6 copies). Primary (N = 65) and metastatic (N = 73) sites were defined based on the biopsy site. A specialized genitourinary pathologist blindly reviewed selected H&E-stained slides and designated tumors as chemotherapy naïve (N = 66) or post-chemotherapy (N = 17) based on treatment related changes. Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Transcriptomic signatures predictive of response to immunotherapy (T cell-inflamed) and platinum sensitivity (PSS, high score suggests increased platinum sensitivity) were applied. Mann-Whitney U and χ² tests were applied, with P-values adjusted for multiple comparisons. Results: Primary and metastatic GCT had slight differences between putative drivers of platinum therapy resistance: KIT (15% vs 1), TP53 (10% vs 17), KRAS (13% vs 9) mutations and MDM2 CNA (4% vs 3), all p> 0.05. When comparing post-chemo vs chemo naïve GCTs, no significant differences in the genomic landscape were observed (p > 0.05). Chemo naïve tumors were shown to be enriched for gene sets associated with KRAS signaling and epithelial-to-mesenchymal transition. Additionally, they trended towards a higher proportion of T cell-inflamed tumors as compared to post-chemo samples (32% vs 18, p = 0.36). The average PSS for chemo naïve was slightly higher than post-chemo (CN: 0.07 Arbitrary Units (AU), N = 62 vs PC: -1.82, N =16, p = .52). Chemo naïve tumors with TP53, KRAS, or KIT mutation or MDM2 CNA had a lower PSS (-4.16 AU, N= 18) than tumors with none of those alterations (2.17, N = 38), p = 0.05. Finally, chemo naïve tumors with MDM2 CNA (N=2, -16.26 AU) had the lowest PSS followed by tumors with mutations in TP53 (N=6, -2.04),KIT (N = 2, -1.77) and KRAS (N=9, -1.05) (mutations were mutually exclusive except for a concurrent KRAS and TP53 mutation). Conclusions: This study provides evidence that chemo naïve GCTs with mutations in TP53, KRAS, KIT or MDM2 CNA have higher expression of genes associated with resistance to platinum-based chemotherapy. These findings contribute to a better understanding of the molecular characteristics of GCTs and may inform prognosis and treatment.