Background: It has been estimated that up to 40% of prostate cancer may be attributed to inherited genetic susceptibility, yet very few variants have been consistently associated with risk and/or adverse outcomes after diagnosis. Moreover, because prostate cancer survival is generally good, risk of developing a second primary cancer (SPC) is an important concern. Identifying men at greater genetic risk of developing an SPC will lead to improved post-diagnostic cancer surveillance practices and lifestyle behavior modifications. Methods: The current investigation leverages genetic and phenotypical data from the UK Biobank (UKB) to examine inherited genetic factors, including rare pathogenic mutations (RPMs) and polygenic risk scores (PRS) with prostate cancer risk and SPC. The individual and joint contribution of (RPM in 26 cancer susceptibility genes and trans-ethnic PRS previously derived for 11 different cancer sites with both risk of prostate cancer and also SPCs among men diagnosed after primary prostate cancer. Cox regression models were used to estimate Hazard Ratio (HR) for prostate cancer, adjusted for age and ancestry. Cumulative incidence of SPC by person-year among prostate cancer patients was estimated from the age of diagnosis and compared with that in men without cancer. Results: Among 228,472 men in the UKB, 17,547 were diagnosed with prostate cancer. RPMs in five genes (ATM, BRCA2, CHEK2, HOXB13 and PTEN) were significantly associated with prostate cancer risk. The rate of prostate cancer among RPM carriers was 15.59% compared with 7.72% in non-carriers (HR=2.26, 95% CI=1.97-2.59). The top decile of PRS_Prostate was associated with a 9.99-fold increase in risk of prostate cancer (95% CI=9.08-11). Having a diagnosis of prostate cancer had a significantly increased risk for two SPCs (bladder and kidney) and reduced risk for lung cancer, p<0.001. Those that developed SPC of bladder cancer had significantly higher PRS_Bladder, p=5.91E-06. The number of RPM carriers (n=77) among SPC bladder cancers was prohibitively small to precisely estimate risk. Conclusions: In this large population-based cohort, both RPMs in largely DNA damage repair genes and PRS contribute to risk of prostate cancer and PRS with second primary bladder cancer among men with prostate cancer. These data both contribute to our understanding of the genetic susceptibility to prostate cancer and reinforce the need for refinement of genetic screening panels.