Phosphatidylethanol (PEth) is a group of alcohol-modified phospholipids present in cell membranes after heavy drinking. Our aim was to demonstrate the presence of human plasma antibodies binding to PEth and to address their specificity and value in detecting subjects engaged in heavy alcohol consumption. Antibodies to PEth were analyzed in plasma from heavy drinkers (n = 20), patients with alcoholic pancreatitis (n = 58) and control subjects (n = 24), using chemiluminescent immunoassay. Heavy drinkers and patients with alcoholic pancreatitis demonstrated significantly lower levels of plasma IgG, IgA and IgM titers to PEth compared with controls (P < 0.001). The specificity of the antibodies to PEth was demonstrated with competitive liquid phase immunoassays and flow cytometry. The plasma IgG, but not IgA or IgM, titers to PEth in heavy drinkers correlated with the whole blood PEth concentration determined by liquid chromatography-mass spectrometry (r = 0.655, P = 0.002). Compared with traditional markers for alcohol abuse (aspartate aminotransferase, gamma-glutamyl transpeptidase and mean corpuscular volume), receiver operating characteristic curve analysis showed that a low plasma IgA to PEth had the highest area under the curve (AUC 0.940, P < 0.001). In conclusion, plasma IgG, IgA and IgM antibodies binding specifically to PEth were found in subjects of all study groups. Subjects with heavy alcohol consumption showed markedly lower plasma immunoglobulin levels to PEth, potentially making them useful as a biomarker to distinguish heavy from moderate alcohol use.