Vascular endothelial growth factor (VEGF) plays important roles in endothelial cell proliferation, vascular permeability, and angiogenesis that may be critical to prostatic carcinogenesis and progression. Plasma VEGF levels were significantly greater in patients with metastatic prostate cancer compared with those with localized disease or healthy controls, and plasma VEGF level at prostate cancer diagnosis was an independent prognostic marker for survival in patients with hormone refractory prostate cancer. We therefore examined the association between prediagnostic plasma VEGF levels and risk of prostate cancer and disease phenotype. Using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, we conducted a nested case-control study among 504 men diagnosed with prostate cancer during 13 years of follow-up and 520 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression. Prediagnostic plasma VEGF levels were similar among cases and controls. Plasma VEGF concentration was not associated with subsequent risk of prostate cancer (third versus first tertile OR, 1.09; 95% CI, 0.80-1.49; P(trend) = 0.65). Furthermore, no association was observed among men with advanced (stage C or D) prostate cancer or among those who died of prostate cancer. Our results indicate that prediagnostic circulating VEGF levels are not associated with prostate cancer development and have limited value in predicting future risk of prostate cancer.