To evaluate an integrated liver biopsy platform that combined CT image fusion, electromagnetic (EM) tracking, and optical molecular imaging (OMI) of indocyanine green (ICG) to target hepatocellular carcinoma (HCC) lesions and a point-of-care (POC) OMIto assessbiopsy cores, allbased on tumor retention of ICGcompared to normal liver, in phantom and animal model. A custom CT image fusion and EM-tracked guidance platform was modified to integrate the measurement of ICG fluorescence intensity signals in targeted liver tissue with an OMI stylet or a POC OMI system. Accuracy was evaluated in phantom and a woodchuck with HCC, 1day after administration of ICG. Fresh biopsy cores and paraffin-embedded formalin-fixed liver tissue blocks were evaluated with the OMI stylet or POC system to identify ICG fluorescence signal and ICG peak intensity. The mean distance between the initial guided needle delivery location and the peak ICG signal was 5.0 ± 4.7mm in the phantom. There was complete agreement between the reviewers of the POC-acquired ICG images, cytology, and histopathology in differentiating HCC-positive from HCC-negative biopsy cores. The peak ICG fluorescence intensity signal in the ex vivo liver blocks was 39 ± 12 and 281 ± 150 for HCC negative and HCC positive, respectively. Biopsy guidance with fused CT imaging, EM tracking, and ICG tracking with an OMI stylet to detect HCC is feasible. Immediate assessment of ICG uptake in biopsy cores with the POC OMI system is feasible and correlates with the presence of HCC in the tissue.