Abstract Objective The purpose of this study was to evaluate the influence of baseline high-density lipoprotein cholesterol (HDL-C) on initial stroke severity and clinical outcomes in acute ischemic stroke. Methods From August 2006 through December 2011, patients with acute atherosclerotic ischemic stroke were included. Total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and HDL-C were checked and National Institutes of Health Stroke Scale (NIHSS) scores were obtained at admission. The primary outcomes were a composite end point of all-cause mortality, recurrent stroke, or occurrence of ischemic heart disease during follow-up. Results Overall, 3093 subjects (mean age 66.8 years) were included and 675 patients (22%) had low HDL-C (≤35 mg/dL) at admission. These patients had higher NIHSS scores. After adjusting for all clinical factors in multivariate logistic analysis, low HDL-C at admission (OR, 1.79, 95% CI, 1.40–2.29) was significantly associated with higher stroke severity (NIHSS score > 6). During the follow-up period, 280 patients (9%) developed one of the components of the composite end point, including 76 (11.3%) in patients with low HDL-C and 204 (8.4%) in patients with normal HDL-C at admission (p < 0.001). In multivariate Cox regression analysis, after adjusting for all clinical factors, low HDL-C at admission (HR, 1.41, 95% CI, 1.02–1.95) was a significant independent predictor of the composite end point. Conclusions Low baseline HDL-C (≤35 mg/dL) at admission was associated with higher stroke severity and poor clinical outcome during follow-up in patients with atherosclerotic ischemic stroke.