Background: HAI of chronomodulated irinotecan (I), 5-Fluorouracil (F) and oxaliplatin (O) (chronoIFO) as well as HAI of O combined with iv F and leucovorin allowed complete macroscopic resections of CRC liver metastases in patients with prior failure on systemic chemotherapy (Bouchahda, Cancer 2009; Goere, Ann Surg 2010). Purpose: To evaluate the resection rate of CRC liver metastases through combining HAI of IFO with cetuximab (Cet) in the first prospective European trial (Lévi, ASCO 2010, TPS#198). Methods: Patients with wt KRAS CRC and unresectable liver metastases receive iv Cet (500 mg/m², D 1 10:00-12:30) and chrono or conventional HAI of I (180 mg/m² D1), F (2800 mg/m²/d D2-D3/4), and O (85 mg/m² D2-3/4) q2 weeks. Grade 3-4 toxicities were managed with dose adaptation and/or supportive measures. Results: 23 patients (9F, 14 M; 33-76 y; PS 0-1) completed full assessment. They had bilateral liver lesions (82%), a median of 7 metastases [2-30; largest diameter, 38 mm (11-150)] and received ≥2 prior iv chemotherapy lines (61%). A median of 4 protocol courses (1-12) was given. Main grade 3-4 toxicities per patient were neutropenia (39%), abdominal pain (30%), fatigue (22%), and leukopenia (17%). An objective tumor response was achieved in 10/23 patients (43.4%). Seven patients underwent liver surgery (30.4%). 17 pts are alive with a median follow up of 16 months. One responding patient with 25 metastases measuring up to 6 cm and involving all liver segments had pathologic complete response in 24 of 25 lesions removed through three-stage hepatectomy. Conclusions: OPTILIV offers a safe and unusually effective treatment option. The trial aims at accruing 48 eligible patients to provide a statistical estimate of the complete macroscopic resection rate and survival in patients with liver metastases from refractory colorectal cancer receiving intravenous cetuximab and hepatic artery infusion of triplet chemotherapy.