Early diagnosis of liver cancer plays a significant role in reducing its high mortality. In this preliminary study, the feasibility of using serum surface-enhanced Raman spectroscopy (SERS) to identify liver cancer was studied. Serum samples were obtained from liver cancer patients and healthy controls. The differences between the SERS spectra of pre-operation and post-operation of liver cancer patients were also analyzed. The general shape and trend of SERS spectra of health control and liver cancer patients were similar. Multivariate analysis, e.g., PLS-SVM, might be useful for the discrimination of serum SERS spectra of pre-operation and post-operation.Early diagnosis of liver cancer plays a significant role in reducing its high mortality. In this preliminary study, the feasibility of using serum surface-enhanced Raman spectroscopy (SERS) to identify liver cancer was studied. Serum samples were obtained from liver cancer patients and healthy controls. The differences between the SERS spectra of pre-operation and post-operation of liver cancer patients were also analyzed. The general shape and trend of SERS spectra of health control and liver cancer patients were similar. Multivariate analysis, e.g., PLS-SVM, might be useful for the discrimination of serum SERS spectra of pre-operation and post-operation.