Clinically insignificant prostate cancer, defined as at most microscopic foci of Gleason grade < or = 3 disease in the radical prostatectomy specimen, has been recognized in some low risk (PSA < 10, biopsy Gleason score < or = 6, clinical Tlc, 2a) patients with minimal biopsy cancer volume. The purpose of this study is to determine if the fraction of cancer in a single positive core biopsy could identify a subset of low risk prostate cancer patients with clinically insignificant disease. Of 1100 patients with Tlc,2 prostate cancer that consecutively underwent radical prostatectomy at Brigham and Women's Hospital between 1989 to 2000, 130 low risk patients whose diagnoses were made on the basis of a single positive core comprised the study cohort. The pathologic findings at radical prostatectomy were enumerated for men with < or = 5% of a single core involved with prostate cancer in order to determine the rate of clinically insignificant prostate cancer in this population. Estimates of PSA survival were calculated using the actuarial method of Kaplan and Meier. Pairwise comparisons were made using the log rank test. For patients with < or = 5% (n = 14) and > 5% (n = 116) involvement of a single positive core, the 4 year PSA failure free survivals were 100% vs. 89% (P = 0.048), respectively. Within the subset of patients with < or = 5% of a single core involved, 7% (1/14) met the criteria for clinically insignificant disease. However, of the remaining 93%, 3, 8, and 2 patients had pathologic stage T2a, T2b, and T3a, respectively. Eleven patients had prostatectomy Gleason scores < or = 3 + 3, two patients had pathologic Gleason scores of 3 + 4, and one patient had a positive surgical margin. Given that only 7% of low risk patients in this cohort with < or = 5% involvement of a single positive core had clinically insignificant disease, the involved core length alone cannot be used to identify patients with clinically insignificant disease. Further studies are needed in order to delineate which patients may not benefit from treatment.