Background: The Prostate Cancer Prevention Trial (PCPT) has challenged the validity of recommended prostate-specific antigen (PSA) thresholds for prostate biopsy (>2.5 ng/ml) given the 17% prostate cancer (pCA) detection rate at PSA of 1.1-2.0. The outcome of patients treated at PSA ≤2.5 is poorly defined, and advantages associated with such an early diagnosis are uncertain. Objective: Compare the outcome of patients with T1c pCA with pretreatment PSA ≤2.5 and 2.6-4.0. Design, setting, and participants: Since 1998, 351 patients with clinical stage T1c and PSA ≤4.0 have been treated at our institution; 84 (24%) of those patients had PSA ≤2.5. Clinical information was obtained from a prospective database. Treatment was radical prostatectomy (RP), brachytherapy, and external-beam radiotherapy (EBRT) in 261 (74%), 67 (19%), and 23 (7%) patients, respectively. Intervention: Definitive therapy for clinically localized pCA. Measurements: Progression-free probability and pathologic end points. Results and limitations: No significant differences between the groups were observed in terms of biopsy (18% vs 22%) or specimen Gleason score 7-8 (44% vs 56%), non-organ-confined cancer (11% vs 13%), indolent cancer (34% vs 24%), or 5-yr progression-free probability (89% vs 93%; p > 0.1 for all). More biologically unimportant cancers (defined as pathologically organ-confined and Gleason ≤6) were identified among patients with PSA ≤2.5 (55% vs 41%, p = 0.050), and indolent cancers were three times more frequent than non-organ-confined cancers among these patients (p = 0.003). Conclusions: The pathologic features and outcome of patients treated at low PSA levels are favorable and similar for patients with PSA ≤2.5 versus 2.6-4.0. However, >50% of the former have potentially biologically unimportant cancer. We failed to identify a therapeutic benefit to the diagnosis of cancers below accepted PSA thresholds for biopsy.