AbstractBackground:Few prospective studies have examined biomarkers of glucose homeostasis or inflammation with prostate cancer risk by tumor stage or grade.Methods:We conducted a case–cohort study to examine associations of prediagnosis hemoglobin A1c (HbA1c), C-peptide, and C-reactive protein (CRP) with prostate cancer risk overall and stratified by tumor stage and grade. The study included 390 nonaggressive (T1–2, N0, M0, and Gleason score <8) and 313 aggressive cases (T3–4, or N1, or M1, or Gleason score 8–10) diagnosed after blood draw (1998–2001) and up to 2013, and a random subcohort of 1,303 cancer-free men at blood draw in the Cancer Prevention Study-II Nutrition Cohort. Prentice-weighted Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI).Results:In the multivariable-adjusted model without body mass index, HbA1c was inversely associated with nonaggressive prostate cancer (HR per unit increase, 0.89; 95% CI, 0.80–1.00; P = 0.04). Analyses stratified by tumor stage and grade separately showed that HbA1c was inversely associated with low-grade prostate cancer (HR per unit increase, 0.89; 95% CI, 0.80–1.00) and positively associated with high-grade prostate cancer (HR per unit increase, 1.15; 95% CI, 1.01–1.30). C-peptide and CRP were not associated with prostate cancer overall or by stage or grade.Conclusions:The current study suggests that associations of hyperglycemia with prostate cancer may differ by tumor grade and stage.Impact:Future studies need to examine prostate cancer by tumor stage and grade, and to better understand the role of hyperglycemia in prostate cancer progression.