Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Treating HCC is challenging because of the poor drug effectiveness and the lack of tools to predict patient responses. To resolve these issues, we established a patient-centric spheroid model using HepG2, TWNT-1, and THP-1 co-culture, that mimics HCC phenotype. We developed a target-independent cell killing (TICK) exclusion strategy to monitor the therapeutic response. We demonstrated that our model reproduced the Barcelona Clinic Liver Cancer (BCLC) molecular classification, displayed known alterations of epigenetic players, and responded to tyrosine kinase inhibitors (TKIs) such as sorafenib, cabozantinib, and lenvatinib in a patient-dependent manner. Importantly, we reported for the first time that our model correctly predicted 34 clinical outcomes to TKIs out of 37 case studies on 32 HCC patients confirming that patient-centric spheroids, combined with our TICK exclusion strategy, are valuable models for drug discovery and opening a near perspective to personalized care.