Purpose: We have shown that preoperative plasma levels of transforming growth factor-β1 (TGF-β1), interleukin 6 (IL)-6, and its receptor (IL-6sR) are associated with prostate cancer progression and metastasis. The objectives of this study were to confirm these findings and to examine the association of changes in plasma levels of these markers after surgery with disease progression in a large consecutive cohort of patients. Experimental Design: Plasma levels of TGF-β1, IL-6, and IL-6sR were measured pre- and postoperatively (6-8 weeks after surgery) in 302 consecutive patients who underwent radical prostatectomy for clinically localized disease. Results: Pre- and postoperative levels of TGF-β 1 were significantly elevated in patients with extraprostatic extension, seminal vesicle involvement, and metastases to lymph nodes. In contrast, preoperative levels of IL-6 and IL-6sR, but not postoperative levels, were significantly associated with tumor volume, prostatectomy Gleason sum, and metastases to lymph nodes. In a postoperative model that included pre- and postoperative TGF-β1, IL-6, and IL-6sR and standard postoperative parameters, postoperative TGF-β1 and prostatectomy Gleason sum were significant predictors of overall and aggressive disease progression. Although, for all patients, plasma levels of all three markers declined significantly after prostate removal, for patients that experienced disease progression, only IL-6 and IL-6sR levels decreased significantly. Conclusions: For patients undergoing radical prostatectomy, preoperative plasma levels of TGF-β1 and IL-6sR are associated with metastases to regional lymph nodes, presumed occult metastases at the time of primary treatment, and disease progression. After prostate removal, postoperative TGF-β1 level increases in value over preoperative levels for the prediction of disease progression.