Background: XIAP acts in both the extrinsic and intrinsic apoptotic pathways as an inhibitor of cell death, protecting cells from a range of triggers. Regulation due to apoptosis resistance may represent a targetable factor for therapeutic intervention in prostate cancer. This study focuses on XIAP as a biomarker and its expression in correlation with disease aggression. Methods: Expression levels of XIAP was analyzed by immunohistochemistry (IHC), graded 1 through 3 according to signal intensity, in radical prostatectomy samples from 90 patients with prostate cancer with a range of phenotypes including: indolent (A), locally advanced (B), progressive to metastatic (C) and de novo metastatic (D). Prognostic data was collected and Fisher’s exact statistical analysis was performed. Secondary analyses included a Fisher’s exact test with a pairwise comparison between individual disease grades and Gleason scores. Results: Higher XIAP protein expression levels on IHC correlated with disease grade and with total Gleason score (p = 0.0008 and p = 0.0002 respectively) by Fisher’s exact test analysis, indicating more aggressive disease phenotypes. Secondary results looked at a pairwise Fisher’s exact analysis comparing XIAP expression levels among disease grades (A-D) and Gleason scores. XIAP expression only significantly differed between those with grade A and D as well as between individuals with grades B and D (measured by Bonferroni-adjusted p-value of 0.003 and 0.018 respectively). Statistical significance was also achieved in XIAP expression levels when comparing among Gleason scores 6 and 8 (p = 0.025), 6 and 9 (p = 0.0125), as well as 7 and 9 (p = 0.030). Conclusions: This study demonstrates a correlation between XIAP expression levels by IHC and aggressiveness of disease, demonstrating clinical significance of XIAP as a prostate cancer biomarker.