Purpose Little data are available on radical prostatectomy findings in men who experience disease progression following active surveillance. Materials and Methods A total of 470 men in our active surveillance program underwent annual repeat needle biopsies to look for progression defined as any Gleason pattern grade 4/5, more than 50% cancer on any core or cancer in more than 2 cores. Slides were available for review in 48 of 51 radical prostatectomies with progression. Results The average time between the first prostate biopsy and radical prostatectomy was 29.5 months (range 13 to 70), with 44% and 75% of the patients showing progression by the second and third biopsy, respectively. There were 31 (65%) organ confined cases, of which 25 (52%) were Gleason score 6. Of 48 cases 17 (35%) had extraprostatic extension, 3 had seminal vesicle/lymph node involvement and 7 (15%) had positive margins. Mean total tumor volume was 1.3 cm 3 (range 0.02 to 10.8). Of the 48 tumors 13 (27%) were potentially clinically insignificant (organ confined, dominant nodule less than 0.5 cm 3, no Gleason pattern 4/5) and 19% (5 of 26) of the radical prostatectomies with a dominant tumor nodule less than 0.5 cm 3 demonstrated extraprostatic extension, 4 with Gleason pattern 4. All 10 tumors with a dominant nodule greater than 1 cm 3 were located predominantly anteriorly. Conclusions Most progression after active surveillance occurs 1 to 2 years after diagnosis suggesting undersampling of more aggressive tumor rather than progression of indolent tumor. Even with progression most tumors have favorable pathology (27% potentially insignificant). A small percentage of men have advanced stage disease (pT3b or N1). The anterior region should be sampled in men on active surveillance.