Purpose: Elevated local and circulating levels of transforming growth factor beta1 (TGF-β1) have been associated with prostate cancer invasion and metastasis. We tested the hypothesis that preoperative plasma TGF-β1 levels would independently predict cancer stage and prognosis in patients who undergo radical prostatectomy. Patients and Methods: The study group consisted of 120 consecutive patients who underwent radical prostatectomy for clinically localized prostate cancer (median follow-up, 53.8 months). Preoperative plasma levels of TGF-β1 were measured and correlated with pathologic parameters and clinical outcomes. TGF-β1 levels also were measured in 44 healthy men without cancer, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 10 men with prostate cancer metastatic to bone. Results: Plasma TGF-β1 levels in patients with lymph node metastases (14.2 ± 2.6 ng/mL) and bone metastases (15.5 ± 2.4 ng/mL) were higher than those in radical prostatectomy patients (5.2 ± 1.3 ng/mL) and healthy subjects (4.5 ± 1.2 ng/mL) (P < .001). In a preoperative analysis, preoperative plasma TGF-β1 level and biopsy Gleason sum both were predictors of organ-confined disease (P = .006 and P = .006, respectively) and PSA progression (P < .001 and P = .021, respectively). In a postoperative multivariate analysis, preoperative plasma TGF-β1 level, pathologic Gleason sum, and surgical margin status were predictors of PSA progression (P = .020, P = .020, and P = .022, respectively). In patients who progressed, preoperative plasma TGF-β1 levels were higher in those with presumed distant compared with local-only failure (P = .019). Conclusion: Plasma TGF-β1 levels are markedly elevated in men with prostate cancer metastatic to regional lymph nodes and bone. In men without clinical or pathologic evidence of metastases, the preoperative plasma TGF-β1 level is a strong predictor of biochemical progression after surgery, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy.