Aims: With the aim to improve peptide receptor radionuclide therapy effects in patients with gastroenteropancreatic neuroendocrine tumor (GEPNET) liver metastases we explored the effect of intra-arterial (IA) administration of [In-111-DTPA]octreotide (In-111-DTPAOC) on tumor uptake in an animal model and in a patient study. Methods: Preclinical study: After administering In-111-DTPAOC intra-venously (IV) or IA, biodistribution studies were performed in rats with a hepatic somatostatin receptor subtype 2 (sst(2))-positive tumor. Clinical study: 3 patients with neuroendocrine liver metastases were injected twice with In-111-DTPAOC. The first injection was given IV, and 2 weeks later, the second was injected IA (hepatic artery). Planar images of the abdomen were made up to 72 hours after injection. Blood samples were taken and urine was collected. Pharmacokinetic modeling was performed on the IV and IA data of the same patient. Based on this model, additional Lu-177 dosimetry calculations for IV and IA administrations were performed. Results: The preclinical study showed a two-fold higher In-111-DTPAOC tumor uptake after IA administration than after IV injection. Patient data showed a large variability in radioactivity increment in liver metastases after IA administration compared with IV administration. Renal radioactivity was not significantly lower after IA administration; Lu-177 dosimetry simulations in 1 patient using a maximum kidney radiation dose of 23Gy showed IA administration resulted in a mean increase in tumor radiation dose of 2.9-fold. Conclusion: Preclinical and clinical data both indicate that IA administration of radiolabeled somatostatin analogs via the hepatic artery can significantly increase radionuclide uptake in GEPNET, sst(2)-positive, liver metastases up to 72 hours postinjection, although the effect of IA administration can differ between patients.