Background: The cell cycle progression (CCP) score and PTEN have never been evaluated together as prognostic markers for risk of metastasis in a radical prostatectomy (RP) cohort of men with National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa), nor in such patients who also received salvage radiation (SRT) alone or with androgen deprivation (SRT+ADT). This study evaluated CCP score and PTEN in both settings. Methods: Participants were treated with RP at Johns Hopkins from 2007-2015. Paraffin-embedded RP tissue was analyzed blind to clinical outcome at Myriad Genetics, for CCP score using qRT-PCR, and PTEN by immunohistochemistry. For overall evaluation of CCP and PTEN in intermediate- and high-risk men a case-cohort sample was selected. Intermediate- and high-risk men with biochemical recurrence who received SRT or SRT+ADT were also sampled to provide a population at particularly high risk. Metastasis-free survival (MFS) was analyzed with the proportional hazards model, weighted for case-cohort design for the overall analysis, and adjusted for CAPRA-S. The clinical cell-cycle risk (CCR) score, a fixed algorithm combining CCP and CAPRA-S was also analyzed in both contexts. Data were analyzed independently by Johns Hopkins and Myriad Genetics. Results: The case-cohort consisted of 209 men, including 47% with Gleason score >4+3, 48% extra-prostatic extension, and 18% with seminal vesicle or lymph node involvement; 42 (20%) developed metastasis. In univariate analyses CCP, CAPRA-S, and PTEN were all highly significant. In multivariable analysis, only CCP and CAPRA-S retained significance (Table section A). CCR was also strongly prognostic, HR=7.9 (95% CI 4.4, 14.5) per unit change, p<0.00001. SRT (56%) or SRT+ADT (44%) were received by 172 men, of whom 78% had Gleason >4+3, 48% extra-prostatic extension, and 34% seminal vesicle or lymph node involvement; 19 (11%) developed metastases. Again, CCP and CAPRA-S, but not PTEN, were statistically significant (Table section B). CCR was also statistically significant, HR=1.7 (95% CI 1.2, 2.4), p=0.002. Conclusions: This is the first comparison, in a recent cohort of intermediate- and high-risk men, of CCP score and PTEN as risk factors for metastasis, and first evaluation in such men receiving SRT. In both multivariable settings, CCP score, but not PTEN, was significantly associated with MFS, adjusted for CAPRA-S. CCR, a fixed algorithm that combines CCP and CAPRA-S was also significant in both settings.