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Pre- and post-radiation therapy (RT) effects on prostate histology have not been rigorously studied, but there appears to be a correlation between escalating radiation dosage and increasing post-RT histologic changes. Despite this dose-response relationship, radiation-induced changes may be heterogenous among different patients and even within a single tumor. When assessing residual tumor it is important to understand biopsy evaluation in the post-RT setting. We present the case of a poorly differentiated prostate adenocarcinoma following proton beam RT in a 45-year-old man with pre-RT Gleason 4 + 3 = 7 disease diagnosed in the setting of an elevated serum prostate-specific antigen level.