Abstract BACKGROUND High-sensitivity assays for cardiac troponin enable more precise measurement of very low concentrations and improved diagnostic accuracy. However, the prognostic value of these measurements, particularly at low concentrations, is less well defined. METHODS We evaluated the prognostic performance of a new high-sensitivity cardiac troponin I (hs-cTnI) assay (Abbott ARCHITECT) compared with the commercial fourth generation cTnT assay in 4695 patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) from the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in NSTE-ACS) and SEPIA-ACS1-TIMI 42 (Otamixaban for the Treatment of Patients with NSTE-ACS) trials. The primary endpoint was cardiovascular death or new myocardial infarction (MI) at 30 days. Baseline cardiac troponin was categorized at the 99th percentile reference limit (26 ng/L for hs-cTnI; 10 ng/L for cTnT) and at sex-specific 99th percentiles for hs-cTnI. RESULTS All patients at baseline had detectable hs-cTnI compared with 94.5% with detectable cTnT. With adjustment for all other elements of the TIMI risk score, patients with hs-cTnI ≥99th percentile had a 3.7-fold higher adjusted risk of cardiovascular death or MI at 30 days relative to patients with hs-cTnI <99th percentile (9.7% vs 3.0%; odds ratio, 3.7; 95% CI, 2.3–5.7; P < 0.001). Similarly, when stratified by categories of hs-cTnI, very low concentrations demonstrated a graded association with cardiovascular death or MI (P-trend < 0.001). Use of sex-specific cutpoints did not improve prognostic performance. Patients with negative fourth generation cTnT (<10 ng/L) but hs-cTnI ≥26 ng/L were at increased risk of cardiovascular death/MI compared to those with hs-cTnI <26 ng/L (9.2% vs 2.9%, P = 0.002). CONCLUSIONS Application of this hs-cTnI assay identified a clinically relevant higher risk of recurrent events among patients with NSTE-ACS, even at very low troponin concentrations.