Background: While conventional transhepatic arterial chemoembolization (TACE) is accepted worldwide as an effective treatment for patients with unresectable hepatocellular carcinoma (HCC), its use in other hepatic tumors is not supported by randomized studies. Preliminary results have shown that new drug-eluting microspheres (DEM) seem to optimize TACE procedures. The aim of this study was to evaluate the capability of HepaSphere™ to load oxaliplatin and their pharmacokinetic outcome. The feasibility and safety of treatment with oxaliplatin-eluting microspheres (OEM-TACE) was also evaluated in patients with unresectable liver metastasis of colorectal cancer and unresectable intrahepatic cholangiocarcinoma. Patients and Methods: An inductively coupled plasma mass spectrometer (ICP-MS) was used to quantify the oxaliplatin bound to microspheres and the oxaliplatin in liver biopsies. Fifteen patients (8 with colorectal carcinoma liver metastases, 7 with intrahepatic cholangiocarcinoma) were treated with 27 sessions of OEM-TACE. Results: The data suggested that the microspheres can bind oxaliplatin entirely. The pharmacokinetic parameters were significantly different between the OEM-TACE patients and a control group of patients treated with oxaliplatin chemotherapy. The mean oxaliplatin concentration within the tumor was twenty-times higher than the extratumoral liver concentration in the OEM-TACE patients. According to response evaluating criteria in solid tumors (RECIST), stable disease was observed in 8 out of the 15 patients (53.3%), a partial response in 2 (13.3%) and intrahepatic or extrahepatic tumor progression in 5 out of the 15 patients (33.3%). No major adverse event (AE G3/4) occurred. Conclusion: TACE with oxaliplatin-loaded microspheres is a safe and feasible treatment without major adverse events and with a favorable pharmacokinetic profile.