Background: Given the morbidities of and limited tumor tissue from prostate biopsies (BXs), circulating biomarkers distinguishing indolent from aggressive disease and predicting disease reclassification (DR) could transform early prostate cancer (PC) management. We have shown that caveolin-1 (Cav-1), a component of caveolae and cellular membrane, is secreted by PC cells, and implicated in the transition from high grade prostatic epithelial neoplasia to prostate cancer and associated with biochemical recurrence after prostatectomy. We evaluated Cav-1’s potential to predict DR during active surveillance (AS). Methods: In a single-institution prospective study, between 2006 and 2014, 825 patients (pts) with early PC were stratified to AS group (GR) I (favorable risk: Gleason score [GS]/single core of 3+3/ < 3 mm or 3+4/ < 2 mm and PSA < 4 ng/mL), II (pt choice), or III (comorbidities preventing local therapy). Pts had entry BX within 6 months of diagnostic BX and repeat BXs every 1–2 years. Tumor volume (TV) or grade increases prompted DR. PSA was measured every 6 months. Baseline plasma Cav-1 was measured in 542 pts using established ELISA in GR I and II pts. Univariate and multivariate logistic regression analyses assessed associations between patient clinicopathologic characteristics and DR. Results: Of 542 pts, 190 (35.1%) met GR I criteria; 352 (64.9%) met GR II criteria. Median age was 64 years; clinical stage cT1c was found in 88.6%; median PSA was 4.1 ng/mL; and GS was 3+3 in 87.3%. After a median of 3.1 years’ follow-up, 163 (30.1%) had met DR. Mean and median Cav-1 levels were 2.2 (SD, 8.5) ng/mL and 0.2 (range, 0, 85.5) ng/mL, respectively. By univariate analysis, log-transformed Cav-1 was a significant predictor for DR (p= .01; OR = 1.33). No association between Cav-1 and PSA or Cav-1 and testosterone was found. On multivariate analysis, adjusting for age, PSA, TV, and GR assignment, log-transformed Cav-1 remained significantly associated with DR (p= .04; OR = 1.27). Longitudinal Cav-1 plasma levels and tissue expression are under study. Conclusions: In a prospective AS cohort, plasma Cav-1 predicted DR independent of other parameters. If validated, results may refine patient selection for AS. Clinical trial information: NCT00490763