Purpose: Men of African ancestry experience an excessive prostate cancer mortality that could be related to an aggressive tumor biology. We previously described an immune-inflammation signature in prostate tumors of African-American (AA) patients. Here, we further deconstructed this signature and investigated its relationships with tumor biology, survival, and a common germline variant in the IFNλ4 (IFNL4) gene. Experimental Design: We analyzed gene expression in prostate tissue datasets and performed genotype and survival analyses. We also overexpressed IFNL4 in human prostate cancer cells. Results: We found that a distinct interferon (IFN) signature that is analogous to the previously described "IFN related DNA damage resistance signature" (IRDS) occurs in prostate tumors. Evaluation of two independent patient cohorts revealed that IRDS is detected about twice as often in prostate tumors of AA than European-American men. Furthermore, analysis in TCGA showed an association of increased IRDS in prostate tumors with decreased diseasefree survival. To explain these observations, we assessed whether IRDS is associated with an IFNL4 germline variant (rs368234815-ΔG) that controls production of IFNλ4, a type III IFN, and is most common in individuals of African ancestry. We show that the IFNL4 rs368234815-ΔG allele was significantly associated with IRDS in prostate tumors and overall survival of AA patients. Moreover, IFNL4 overexpression induced IRDS in three human prostate cancer cell lines. Conclusions: Our study links a germline variant that controls production of IFNλ4 to the occurrence of a clinically relevant IFN signature in prostate tumors that may predominantly affect men of African ancestry.