Progression of liver failure to coma is a dynamic process. Its prognosis depends primarily on early diagnosis, real-time monitoring of the disease, and appropriate therapy. Current detection methods and repeated blood sampling do not effortlessly meet the clinical requirements. This pilot study aimed to assess the potential of exhaled breath analysis by extractive electrospray ionization mass spectrometry (EESI-MS) as a noninvasive clinical tool to diagnose and provide real-time monitoring of liver failure. A total of 24 healthy controls, 20 chronic hepatitis B patients, and 20 liver failure patients were enrolled in this study. Patients were diagnosed prior to exhaled breath collection; serological biochemical indicators and clinical characteristics were recorded. Exhaled breath samples were detected by EESI-MS; principal component analysis and partial least square discriminant analysis was used to process the final data. Twenty-two mass-to-charge ratio (m/z) values differed significantly between liver failure patients and healthy controls (variable importance plot (VIP)>3.5, P<0.001), and eight metabolites were identified to be 1-butylene, acetone, glycolaldehyde, isoprene, butanone, 2-ethylacrylic acid, ethylmethylacetic acid, and 2,3-octanedione. Four m/z values differed significantly between liver failure and chronic hepatitis B patients (VIP > 3.5, P<0.001) and 2 metabolites were identified to be isoprene and glycolaldehyde. Exhaled breath analysis may be valuable as a noninvasive clinical tool to diagnose and provide real-time monitoring of liver failure.