BACKGROUND Ischemic cardiomyopathy (ICM) resulting from coronary artery disease is a major cause of heart failure. The identification and quantification of differentially expressed proteins in patients with ICM may potentially lead to more effective diagnostic workup and treatment. AIMS liquid chromatography coupled to tandem mass spectrometry analysis was applied to identify differentially expressed proteins in individuals with ICM. METHODS To identify proteins involved in the molecular mechanisms of ICM, we quantitatively analyzed the left ventricular proteome profiles of patients with ICM who had undergone heart transplantation. Liquid chromatography coupled to tandem mass spectrometry, which presents better comprehensiveness and accuracy of quantification than 2-dimensional electrophoresis, in combination with bioinformatics was applied to analyze cardiac samples and identify proteins that were differentially expressed in the left ventricles of 6 patients with ICM compared with 7 normal heart donors. RESULTS A total of 1723 proteins was successfully quantified in 2 repeated experiments. Out of those, 104 proteins were upregulated and 63 proteins were downregulated in the left ventricles of individuals with ICM. For all these altered proteins, gene ontology (GO) analysis, the Kyoto Encyclopedia of Genes and Genomes pathway mapping, and protein interaction analysis were performed, which showed that most of the proteins were related to the extracellular matrix, metabolism, immune response, muscle contraction, cytoskeleton organization, transcription/translation, and signal transduction. Most importantly, in response to an ischemic stimulus, the C1 inhibitor SERPING1 helped to compensate for increases in complement activation through complement inhibition. CONCLUSIONS Collectively, these differentially expressed proteins represent potential novel diagnostic and therapeutic targets for the treatment of patients with ICM.