Background: Some patients from our radical prostatectomy (RPx) series with organ-confined (pT2) prostate cancer and negative surgical margins show a PSA (prostate specific antigen) relapse. Aim of the study was to analyze this cohort of patients that otherwise would have been considered to be cured. Patients and Methods: Since the introduction of PSA measurement in the follow-up after RPx, 475 pelvic lymph node dissections with subsequent RPx were performed in our department from 1988 to 1997. Of these, 227 were classified as pT2, 34 (15%) exhibited positive surgical margins, and 4 others were excluded due to an inadequate follow-up. Of the remaining 189 patients (study cohort), 19 (10%) developed a biochemical progression, defined as a minimum of 2 consecutive PSA measurements ≥ 0.1 ng/ml. Only in one of them a G3 tumor was present. Median follow-up was 19.1 months. Results: The Kaplan-Meier analysis of biochemical progression showed that after 1, 2 and 5 years, 95% (confidence interval (Cl) 91-99%), 91% (Cl 86-96%), and 77% (Cl 55-89%) of the patients were free of progression, respectively. This means that roughly one fourth of pT2 tumors will become progressive despite negative surgical margins. These 19 patients were subdivided into 4 groups: 1: biopsy-proven local recurrence (n = 2); 2: suspected local recurrence defined as slowly rising PSA ≤ 2 ng/ml, but negative biopsies (n = 12); 3: distant metastasis proven by radiologic imaging (n = 1); 4: suspected distant metastasis defined as rapidly rising PSA > 9 ng/ml without direct radiologic evidence (n = 4). Preoperatively all patients from groups 3 + 4 had negative bone scans and 4/5 had preoperative PSA values < 10 ng/ml. In total 7 patients with proven recurrence or with proven metastasis had positive biopsies. Conclusion: A pathological diagnosis of organ-confined prostate cancer (pT2) and a meticulous analysis of negative surgical margins do not exclude the occurrence of local relapses in 7% (14/189), and there is evidence for suspect hematogenic spread of PC cells in at least 2% (4/189) of patients.