The method detects acute hepatocyte death based on quantification of circulating, cell-free DNA (cfDNA) fragments carrying hepatocyte-specific methylation patterns (3 genomic loci that are unmethylated specifically in hepatocytes). It can be used for detection after liver transplantation, during acute rejection of an established liver transplant, and also in healthy individuals after partial hepatectomy. Measurements correlate with traditional measurements of liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Measurements of hepatocyte-derived cfDNA can provide specific and sensitive information on hepatocyte death, for monitoring human liver dynamics, disease, and toxicity.