In this study, we employed both untargeted and targeted analysis of low abundance serum proteins to identify potential biomarkers for HCC. We employed a two-phase proteomics approach to identify low abundance serum proteins as potential biomarkers for HCC.The first phase involved DDA-based untargeted proteomics analysis of serum samples from HCC cases and patients with CIRR. Label-free quantification (LFQ) was performed to identify statistically significantly differentially expressed proteins. In the second phase, a targeted proteomics analysis was conducted using PRM on the same cohort of samples targeting proteins selected in the untargeted study along with AFP and other previously reported biomarker candidates.