This investigation was designed to identify potential directions for future modification of the percutaneous prostate cryoablation procedure. An analysis of prostate cancer location and volume in radical prostatectomy specimens was performed to evaluate the potential clinical consequences of these proposed modifications. A list of recommendations for improvements in the prostate cryoablation procedure was compiled from informal discussions held with participants in 9 training courses and conferences on prostate cryoablation over 18 months. Subsequently, a population of 112 consecutive, sagittally sectioned whole-mount radical prostatectomy samples was evaluated for prostate cancer volume, number of individual foci, and location to examine the disease-specific outcomes of these proposed modifications. The most common areas for potential alterations in the current cryoablation technique include modifications that would further simplify the procedure, continue to reduce real and perceived toxicity, and augment efficacy. Importantly, modifications designed to reduce treatment side effects could conflict with efforts designed to improve eradication of prostate cancer. Pathologic analysis revealed multifocal cancer in 79.5% of the samples, with 66% of cases exhibiting cancer within 5 mm of the urethra. The median volume of the index cancer was 1.6 cm³, whereas the median volume of the smaller ancillary lesions was 0.3 cm³. Prostate parenchymal-sparing alterations, proposed to reduce incontinence and erectile dysfunction by targeting the index cancer, would likely eradicate clinically significant cancer in 79% of men. The recent enthusiasm for prostate cryoablation as a reasonable minimally invasive treatment option for men with clinically localized cancer is likely to result in modifications of the established surgical technique. Knowledge of the anatomic location and cancer volume within the prostate gland is an important adjunct to planning such alterations. It is possible that parenchymal-sparing modifications to total gland prostate cryoablation can eradicate clinically significant cancer in most men, with a reduction in toxicity and cost.