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Lymphovascular invasion is an adverse pathologic feature in prostate cancer, but its independent molecular drivers remain unclear due to strong confounding by tumor grade and stage. We performed a confounder-adjusted transcriptomic analysis of 403 TCGA-PRAD samples. Differential expression was adjusted for Gleason score and pathological T stage. A transcriptional profile associated with LVI was derived and tested in multivariable logistic and Cox proportional hazards models for biochemical recurrence-free survival, with bootstrap internal validation. After multivariable adjustment, 129 genes were independently associated with LVI. This gene set was overwhelmingly enriched for interferon-alpha/beta signaling and antiviral response pathways. A continuous composite score derived from this profile predicted a reduced risk of biochemical recurrence independently of standard clinicopathological factors (adjusted HR per unit = 0.911, 95% CI: 0.835-0.993, p = 0.033). Multi-omics integration revealed subtle promoter hypomethylation and strong correlations between methylation and expression for key interferon genes, supporting transcriptional regulation. We identify a robust, interferon-response transcriptional profile that specifically defines LVI in prostate cancer after accounting for major clinical confounders. This transcriptional signature provides independent prognostic information, refines the biological understanding of LVI, and presents a novel targetable pathway for further investigation.