AIMS: The patterns and prognostic significance of low high-density lipoprotein (HDL) cholesterol levels have not been well characterized. We sought to determine the prevalence and prognostic significance of low HDL cholesterol levels in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). METHODS AND RESULTS: We evaluated HDL levels among NSTE ACS patients [ischaemic ECG (electrocardiogram) changes and/or positive cardiac markers] from the CRUSADE [Can Rapid Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC(American College of Cardiology)/AHA(American Heart Association) Guidelines] initiative treated at 555 US hospitals from January 2001 through June 2006. Clinical and angiographic characteristics, treatments, and in-hospital outcomes were analysed by categories of HDL levels measured during hospitalization. Among 93 263 NSTE ACS patients with HDL measurements, 16 854 (18.1%) had very low HDL levels (10-29 mg/dL), 32 185 (34.5%) had low HDL levels (30-39 mg/dL), 35 875 (38.5%) had normal HDL levels (40-59 mg/dL), and 8349 (9.0%) had high HDL levels (60-100 mg/dL). Patients with very low HDL levels were younger, more often male, and more commonly obese and diabetic. Patients with very low HDL levels had the greatest risk of multi-vessel coronary disease on angiography and in-hospital mortality compared with patients with normal and high HDL levels. CONCLUSION: Almost one-fifth of patients with NSTE ACS have very low HDL levels--a finding that adds incrementally to a greater burden of atherosclerosis and a higher risk of mortality. Consequently, strategies for mitigating the adverse prognosis associated with very low HDL levels warrant further exploration in patients with ACS.