Esophageal adenocarcinoma (EAC) exhibits marked male predominance with male-to-female ratios reaching 8.5:1, yet the molecular basis underlying this sex disparity remains poorly characterized. We analyzed 92 EAC specimens using mass spectrometry–based proteomics, comprising 47 female and 45 male tumors from treatment-naïve patients. Differential expression, pathway enrichment, immunohistochemical, and survival analyses were used to identify sex-associated proteomic features and prognostic signatures. Proteomic profiling revealed focal yet biologically meaningful sex differences in esophageal adenocarcinoma. After multiple testing correction, three proteins were differentially expressed: the autosomal protein pregnancy zone protein (PZP), enriched in female tumors, and the Y-chromosome–encoded proteins DDX3Y and RPS4Y1, which were overexpressed in male tumors. At nominal significance, proteins upregulated in female tumors showed marked enrichment of immune-related pathways. Proteins correlated with PZP expression formed a network dominated by complement cascade. Clinically, elevated PZP expression was associated with significantly poorer overall survival, most pronounced in male patients and independent of sex-specific survival differences. Proteome-wide survival analyses further demonstrated distinct sex-specific prognostic landscapes. Our study provides the first comprehensive characterization of sex-associated proteomic differences in EAC. Sex shapes immune-related pathways, prognostic proteomic signatures, and survival associations. PZP emerges as a sex-differential, complement-associated protein with adverse prognostic significance, highlighting sex as a biologically and clinically relevant variable in EAC