Background: A biopsy-based RT-PCR assay (Oncotype DX Prostate Assay) providing a Genomic Prostate Score (GPS) as a measure of tumor aggressiveness has been validated as a predictor of adverse pathologic and oncologic outcomes. We sought to evaluate the change in GPS results among men with favorable-risk prostate cancer (PCa) managed with active surveillance (AS). Methods: We identified men with low and intermediate-clinical risk PCa managed with AS at our institution receiving a minimum of two GPS tests on serial prostate biopsy. GPS ranges from 0 (least) to 100 (most aggressive disease). We described the change in assay results and clinical risk designation over time and reported the subsequent clinical outcome (definitive treatment versus continued AS). For men receiving treatment with radical prostatectomy (RP) the occurrence of adverse pathological findings was defined by the presence of high grade (Gleason pattern ≥ 4+3) or non-organ confined disease ( ≥ pT3a). Results: 31 men were identified who underwent serial GPS testing at a median of 12 months. The median change in GPS was an increase of 1 point (IQR -7, 13). Fourteen (45%) patients experienced an increase in NCCN risk classification, including 3 from very-low to intermediate and 11 from low to intermediate risk. Following serial GPS testing 7 patients (23%) underwent radical prostatectomy. Among surgically treated patients, 3 had adverse pathology due to pT3a disease and the mean change in GPS prior to treatment was an increase of 13 points (IQR -7, 18); all of whom were intermediate clinical risk at the time of surgery. This study was limited by the small sample size and the uncontrolled decision to pursue definitive therapy. Conclusions: Serial change in a tissue based gene expression assay on serial biopsy during AS was non-static. Magnitude of GPS change may identify men at risk for adverse pathological findings, although larger series are required to validate such an endpoint during AS.