Subjects must have prostate cancer amenable for ultrasound ablation defined as:

diagnosed by transrectal ultrasound-guided prostate biopsy via standard 12 core biopsy and targeted biopsy of any MRI-visible or tracked lesions; pathological diagnosis must be confirmed by Laboratory of Pathology, NCI;

Gleason Score \<= 7;

MRI-visible or MRI-tracked prostate cancer. This includes prostate cancer found on targeted biopsy of MRI-visible or MRI-tracked lesion. Histologically positive standard biopsy cores of Grade Group \>= 2 prostate cancer must be from an area overlying or within 1cm of an MRI-visible or tracked lesion(s) and reviewed by NCI urologic pathologist. (Left / Right, Base, Mid-Gland, Apex). Systematic and targeted cores of Grade Group 1 prostate cancer outside of proposed ablation zone do not affect inclusion status, as these can be observed by conventional guideline management.

organ confined clinical T1c or clinical T2a prostate cancer that is visualized on MRI. Note: Participants after prostate cancer treatment with local recurrence or residual tumor which is visible on MRI are eligible.

PSA \< 20 ng/ml or PSA \>20 with a PSA density \<0.15.

Adults (\>= 18 years of age)

Participants must have adequate organ and marrow function as defined below:

Platelets \>= 50,000/mcL

Hemoglobin \>= 8 g/dL

Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl)\* \>= 30 mL/min/1.73 m\^2

GFR=glomerular filtration rate; ULN=upper limit of normal.

\*Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.

Subjects must be able to understand and willing to sign a written informed consent document.

Subjects must be co-enrolled to NCI protocol 16-C-0010 "Care of the Prostate Cancer Patient and Prospective Procurement of Prostate Cancer Tissue."

Minimum age: 18

Targeted lesion ablation length from apex to base of \>5 cm or lesion extending \>3 cm from the urethra.

Target ablation volume greater than 100 ml.

Presence of calcifications that would impede ultrasound transmission between the urethra and ablative target.

Participants are unable to tolerate MRI (foreign body, i.e., pacemaker or other implanted device; claustrophobia; inability to tolerate rectal coil; etc.)

Acute urinary tract infection

Lower urinary tract symptoms defined by an IPSS \> 20

Participants with uncontrolled coagulopathies (including liver dysfunction, or untreated hereditary coagulopathies which have a standard of care treatment) per surgeon discretion based on bleeding risk.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation (within time frame) that would limit compliance with study requirements.