A complete response following neoadjuvant therapy occurs only in a fraction of patients with esophageal adenocarcinoma (EAC). Further targeted treatment options are needed to improve treatment response and patient survival. Mouse double minute 2 homolog (MDM2) is a known oncogene. Its upregulation results in a more aggressive cancer phenotype. It is currently under investigation as a potential therapeutic target. However, initial findings have not been groundbreaking. Therefore, this study aimed to identify further potential therapeutic targets in the subtype of MDM2-amplified EAC. Methods: We screened 656 patients with operable esophageal adenocarcinoma for their MDM2-amplification status using Fluorescence in situ Hybridization (FISH). 57 tumors (8.7%) were MDM2-amplified. The proteome of 35 MDM2-amplified and 37 non-amplified tumors was analyzed using mass spectrometry. 22.2% of the included patients were primarily resected, and 77.8% were neoadjuvant treated. Results: The comparison of MDM2-amplified and non-amplified tumors revealed various differently expressed proteins and pathways. Hornerin, Bystin, and subtypes of keratins (KRT1, KRT2, KRT9, KRT10) were significantly downregulated. Whereas Choline transporter-like protein 2 (CTL2), Cullin-associated NEDD8-dissociated protein 1 (CAND1), FAD- and RhoGTPase-binding protein 1 (FARP1), and Contactin 1 were upregulated in MDM2-amplified EAC. Enrichment analyses revealed that MDM2-amplified esophageal adenocarcinomas showed a more pronounced immunosuppressive phenotype due to the downregulation of interferon signaling pathways and antigen presentation. Furthermore, distinct metabolic pathways like carbon, propanoate, tryptophan, and tyrosine metabolism were upregulated in MDM2-amplified tumors. Conclusion: In this study, we investigated the whole proteome of MDM2-amplified compared to non-amplified esophageal adenocarcinomas. We described numerous potential future therapeutic targets, suggesting patients with MDM2-amplified tumors could potentially benefit from, exemplary, Mitogen-activated protein kinase kinase (MEK) inhibitors or tryptophan metabolism inhibitors. Future mechanistic studies are needed to validate these findings.