Purpose We correlated nadir post-cryoablation prostate specific antigen with long-term biochemical disease-free survival in a risk stratified cohort of patients with prostate cancer treated with cryoablation. Materials and Methods The records of 2,427 patients treated with cryoablation from the Cryo On-Line Data Registry were studied for biochemical disease-free survival based on nadir + 2 criteria using prostate specific antigen determinations out to 60 months after cryoablation. Results For nadir prostate specific antigen less than 0.1 ng/ml, the 36, 48 and 60-month biochemical disease-free survival was 93%, 91.8% and 91.8%, respectively, for low risk disease; 88%, 81% and 76%, respectively, for intermediate risk; and 82%, 76% and 71%, respectively, for high risk disease. For prostate specific antigen 0.1 to 0.5 ng/ml the 36, 48 and 60-month biochemical disease-free survival rates were 92%, 91.5% and 86%, respectively, for low risk; 78%, 72% and 67%, respectively, for intermediate risk; and 64%, 61% and 51%, respectively, for high risk disease. For a prostate specific antigen of 0.6 to 1.0 ng/ml the 24-month biochemical disease-free survival was 70.5% for low risk, 56.1% for intermediate risk and 46.7% for high risk disease. A prostate specific antigen of 1.1 to 2.5 ng/ml was associated with a 12-month failure rate of 29.6%, 38% and 74.8% for low, intermediate and high risk groups, respectively. Conclusions Nadir prostate specific antigen after prostate cryoablation is prognostic for biochemical disease-free survival. However, by itself it cannot be used as a definition of disease-free survival since it has not been correlated with disease specific or metastasis-free survival. A prostate specific antigen of 0.6 ng/ml or greater correlated with a 29.5% biochemical failure rate at 24 months regardless of risk stratification and, therefore, these cases require close followup.