In peptide receptor radionuclide therapy of neuroendocrine tumors, improvements have been made by increasing the affinity for receptors and by protecting critical organs (e. g., kidneys). However, tumor parameters involved in radiopeptide uptake are still under investigation. Interferon-alpha (IFN alpha) is used as biotherapy for neuroendocrine tumors. Several mechanisms of action are described, but the potential effect of IFN alpha on tumor uptake of labeled peptide has not been studied in vivo yet. Methods: Twenty-six male CA20948 tumor-bearing Lewis rats were imaged before and during IFN alpha treatment using quantitative small-animal PET with [(68)Ga-DOTA, Tyr(3), Thre(8)] octreotide. Imaging was performed at days 0, 3, and 7. Animals were divided into 3 groups according to the treatment: control (injected daily with saline), half (4 d of IFN alpha treatment from day 0 to day 3, then saline), and full (7 d of IFN alpha). A daily dose of IFN alpha (1.5 mIU) was administered subcutaneously. Quantitative PET results are expressed as percentage injected dose per cm(3) and normalized to baseline (day 0) values. Tumor size was monitored by PET and caliper measurements. Results: Gross tumor uptake and tumor volumes increased in all groups over the 7-d period. On day 3, mean +/- SD ratios to day 0 were 1.2 +/- 0.2, 1.3 +/- 0.5, and 1.2 +/- 0.4, respectively, for control, half, and full groups. On day 7, respective values were 1.1 +/- 0.2, 1.3 +/- 0.6, and 1.5 +/- 0.4. At day 3, a comparison among groups showed no statistically significant difference. At day 7, the full group showed a significantly higher ratio in activity concentration than the control group (P = 0.021). A good correlation was found between tumor volumes assessed by small-animal PET and caliper measurements (R = 0.89, P < 0.0001). Conclusion: As expected, over a period of 7 d, both tumor volumes and radiopeptide uptake increased in all animals. However, the activity concentration increased significantly more at day 7 in animals treated for 7 d with IFN alpha, compared with controls. This is the first, to our knowledge, in vivo indication that IFN alpha is able to increase tumor uptake of the labeled analog in a small-animal model of neuroendocrine tumors. The mechanisms underlying this effect (flow, vascular permeability, receptor upregulation) remain unknown and need to be further investigated.