BACKGROUND Serum prealbumin (PA), which is a nutritional index, has been found to be associated with severities and prognoses of various diseases. However, there are no reports about the relationship between PA and angiographic severity of coronary artery disease. MATERIAL AND METHODS This cross-sectional study included 867 patients with acute coronary syndrome (ACS) who underwent coronary angiography. Patients were divided into quartiles of PA and coronary artery stenosis was determined by angiographic Gensini score, the presence of high Gensini score (Gensini score ≥120), and triple-vessel disease. Multivariate linear and logistic regression analyses were performed to explore the relationship between PA and disease severity in a coronary angiogram. RESULTS There was a significant and independent negative correlation between PA and Gensini score in multivariate linear regression (p=0.015). Logistic regression analysis revealed that crude odds ratios of triple-vessel disease and high Gensini score were 2.47 (95% CI: 1.66-3.67) and 1.83 (95% CI: 1.50-3.49), respectively, in the first quartile of PA compared with the fourth quartile and the results remained significant for high Gensini score after adjustment for confounding factors. In addition, estimated glomerular filtration rate, liver function, and high-sensitivity C-reactive protein (hs-CRP) had no interactive relationships in the above associations. Patients with lower levels of albumin or higher levels of hs-CRP or the ratio of hs-CRP to PA (hs-CRP/PA) also had more severe coronary atherosclerosis. CONCLUSIONS PA is negatively and independently associated with angiographic severity in patients with ACS, indicating for potential use in estimating the burden of coronary atherosclerosis.