Background: The combination of hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin (IFO) with iv cetuximab (Cet) achieved prolonged survival in colorectal cancer patients (pts) with extensive liver metastases (LM-CRC) despite prior chemotherapy (Lévi et al. Ann Oncol 2016). Systemic drug and metabolite exposure is unknown during the HAI delivery of combination chemotherapy in patients with extensive liver metastases. Methods: We estimated the plasma pharmacokinetics of IFO and their main metabolites during the first course of chronomodulated triplet HAI, and related them to toxicity (CTC-AE grades) and efficacy. Results: 11 patients, 7 males, 4 females, aged 33 to 72 years, had PS = 0, one to three prior intravenous chemotherapy protocols, a median number of 7 liver metastases, involving a median number of 7 liver segments. Maximal concentration (Cmax) and area under the curve (AUC) for all drugs and metabolites were not related to response, progression-free survival and overall survival. In contrast, consistent associations were found between the AUC of irinotecan, SN38, total oxaliplatin and platinum ultrafiltrate (P-UF), and leukopenia grade after first course (Spearman test, |r| > 0.50; 0.05 < p < 0.08).Moreover, P-UF Cmax and AUC significantly predicted for the grades of diarrhea (|r| = 0.82, p = 0.004 and |r| = 0.73, p = 0.017, respectively), and anemia (|r| = 0.87, p = 0.001 and |r| = 0.78, p = 0.008, respectively). AUCs and/or Cmax of the HAI drugs and/or their main metabolites displayed consistent relations with leukopenia, anemia, diarrhea, but also fatigue and anorexia over the initial 3 courses as well. Conclusions: Hematologic and intestinal toxicities of this new highly effective protocol mostly related to the systemic exposure of the three HAI drugs. In contrast, the high antitumor efficacy involves the direct drug exposure of liver metastases. Mathematical modelling will help personalize HAI combination chronotherapy for jointly enhancing efficacy and reducing toxicity. Clinical trial information: NCT00852228