A major challenge in prostate cancer (CaP) treatment is evident due to molecular-based transformations resulting in the loss of response to and/or expression of the androgen receptor phenotype. It is generally recognized that many CaPs transform from androgen-dependent/sensitive (AS) to androgen-independent/insensitive (AI) phenotypes with age. Further, is now appreciated that androgen independent CaP is relatively refractory to in situ therapies. Recently, the presumption that freezing serves as a ubiquitous lethal stress in prostate cancer (CaP) has been challenged by anecdotal clinical experience and experimental evidence demonstrating time–temperature related cell death dependencies. As such, in this study we investigate the difference in freeze sensitivity between AI and AS CaP cell lines to determine the impact of CaP AR responsiveness on cryoablation efficacy. We hypothesized that molecular changes resulting in a more aggressive phenotype following androgen ablation treatments is responsible, in part, for the observed increase in cell tolerance to cryotherapy.A series of studies were designed to identify the cellular mechanisms contributing to variations in freeze response. Survival estimates of AS and AI CaP cell lines following freezing exposure were determined using cell viability assays and fluorescent microscopy. Cell death and stress pathway involvement was detailed through molecular analysis and inhibition studies of select key proteins.LNCaP (passaged multiple times) cells demonstrated a phenotypic shift to freeze resistance that matched the freeze response of AI PC-3 cells along with a transformation to androgen independence, while PC-3 cells stably expressing a functional androgen receptor matched the freezing sensitivity of the AS LNCaP cell line. Importantly, AI cell lines survived and recovered freezing exposure to temperatures to −40°C, whereas AS cell lines exposed to temperatures colder than −20°C did not survive. Cell death assays using an apoptotic inhibitor revealed that apoptosis was significantly increased in both AS cell lines following freezing compared to AI counterparts. These results were further confirmed through caspase activity assays and apoptotic fluorescent probes. Protein analysis indicated the androgen receptor is manipulated post-freezing exposure. Finally, AKT inhibition significantly increased the freezing sensitivity of AI CaP cells.These observations are the first to describe a phenotypic variation in CaP cellular response to freezing. Our study demonstrates that AS cancers are far more sensitive to a freezing insult, which might support an interpretation that a younger patient pool may prove to be ideal candidates for cryoablation as a primary therapy. Specifically, CaP cryoablation may prove most effective in CaPs that have not yet progressed to a more resistant AI phenotype. In addition, a further understanding of the role of the AR in freezing responses may increase options for neo-adjunctive treatments targeting the AR signaling pathway.