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The purpose of this study was to assess the relationship of total prostate volume (TPV) and oncologic outcomes following focal prostate cryoablation.A query of the Cryo On-Line Database (COLD) registry for men who underwent primary focal prostate cryoablation revealed 829 patients with complete data. The impact of TPV on oncologic outcomes including progression-free survival (PFS) and post-cryoablation biopsy outcome was assessed using Kaplan-Meier curves and Cox and logistic regression models.The median follow-up time was 25.2 months (interquartile range [IQR], 12.7-48.2 months). The median age at time of treatment was 68 years (IQR, 63-74 years) with median prostate-specific antigen (PSA) 5.6 ng/mL (IQR, 4.4-7.5 ng/mL), and median TPV 35 mL (IQR, 26.5-46 mL). PFS was achieved in 83.2%, with positive post-cryoablation biopsy detected in 81 (35.7%) of 228 patients. Higher TPV was associated with higher biochemical progression (BP) using the Phoenix definition (39 vs. 34.5 mL; P = .003) and was an independent predictor of BP (hazard ratio, 1.01; P = .02). Conversely, men who had a positive post-cryoablation biopsy had significantly smaller median TPV on univariate and multivariate analyses (31 vs. 39 mL; P < .001), (odds ratio, 0.97; P = .001), respectively. Higher median pretreatment PSA density was associated with higher BP (0.18 vs. 0.16; P = .005) and positive post-cryoablation biopsy rates (0.2 vs. 0.16; P = .003).Prostate volume has contradictory effects on BP and post-cryoablation biopsy outcome in men who underwent primary focal prostate cryoablation. Remnant viable tissue in larger prostates continues to produce more PSA over time, which may impact BP. This may raise the need to develop a new definition for oncologic success following focal gland therapy rather than the American Society for Radiation Oncology (ASTRO) and Phoenix definitions.The purpose of this study was to assess the effect of total prostate volume on biochemical progression and local disease control following primary focal prostate cryoablation. After analyzing 829 men, larger prostate volume is associated with higher rates of biochemical progression, but lower rates of positive biopsy. Remnant viable tissue in larger prostates continues to produce more prostate-specific antigen over time which may impact biochemical outcomes.