OBJECTIVES: To assess the role of clinical parameters and pathologic stage in predicting a positive vesicourethral anastomosis (VUA) biopsy in patients with a rising prostate-specific antigen (PSA) level after radical prostatectomy. METHODS: Forty-five patients were referred for a rising PSA level after radical prostatectomy. Transrectal ultrasound evaluation included visualization of the VUA and VUA quadrant biopsies. The rate of positive biopsies (per core and per patient) was correlated with race, PSA level, and the radical prostatectomy pathologic stage. RESULTS: Overall, 53% of patients had a positive biopsy. In multivariate analysis, the dominant independent and synergistic clinical parameters determining positive biopsy rates were a PSA greater than 1 ng/mL at the time of biopsy and the pathologic stage (P = 0.04 and P = 0.02, respectively). Using a PSA cutoff point of 1.0 ng/mL, those patients with organ-confined disease and a PSA of 1.0 ng/mL or less showed no positive cancer cores (low-risk group). Conversely, 89% of patients with extraprostatic extension and a PSA greater than 1.0 ng/mL had a positive biopsy (P <0.01) (high-risk group). Patients with organ-confined disease and a PSA greater than 1.0 ng/mL or extraprostatic extension and a PSA 1.0 ng/mL or less (intermediate-risk group) had a significantly higher chance of having residual cancer than the low-risk group (P <0.025). CONCLUSIONS: The PSA level at the time of biopsy and the pathologic stage of the radical prostatectomy specimen were the strongest determinants of a positive biopsy. A combination of PSA and pathologic stage is useful for decisions regarding VUA biopsy. Patients with organ-confined disease and a PSA of 1.0 ng/mL or less do not appear to benefit from a VUA biopsy, and patients with extraprostatic extension and a PSA greater than 1.0 ng/mL have such a high probability (89%) of local recurrence at the VUA that biopsy may be unnecessary. It appears that VUA biopsy can be restricted to those patients with an intermediate risk (organ-confined disease with PSA greater than 1 ng/mL or extraprostatic extension with a PSA less than 1 ng/mL).