Iodine-131 ((131)I) administered to patients for imaging or treatment, concentrates in the gastrointestinal tract, including the salivary glands, stomach and bowel. In Nuclear Medicine practice this biological property of iodine causes side effects when the therapeutic dose of (131)I is large. This occurs during the treatment of patients with differentiated thyroid carcinoma (DTC). During this clinical application, the dose of (131)I is higher than 3.7 GBq. Side effects of this treatment with respect to the stomach, include gastritis as an inflammatory reaction to radiation, anorexia due to gastric atrophy and rarely megaloblastic anemia due to lack of the endogenous factor. Side effects can also include xerostomia. We have recently tried to prevent gastric side effects by prescribing proton pump inhibitors (PPI) for patients with DTC prior to treatment with (131)I. PPI block the excretion of hydrochloric acid from the gastric mucosa and are utilized for the prevention and treatment of gastritis, gastric ulcers and gastroesophageal reflux. Whole body scans before or after the administration of PPI, showed that PPI do not interfere with the biologic distribution of (131)I. These findings were not surprising. Recent studies in animals and humans have shown that the accumulation and concentration of iodine by the thyroid gland is the result of the selective action of sodium iodine symporter (Na+I+symporter, NIS). Furthermore, it was shown that the accumulation and concentration of (131)I in the parietal cells of the gastric mucosa, the ductal cells of the salivary glands and the alveolar epithelial cells of the mammary glands, is analogous to the biologic action of NIS in the thyroid cells. The gastric mucosa accumulates iodine from the capillaries via the extracellular/extravascular space and finally excretes it into the lumen of the stomach, from where it is passively transferred into the bowel, where it is partially reabsorbed to once again enter its metabolic cycle. On the contrary, as it is now known, the PPI have an entirely different metabolic action, which is unrelated to that of the NIS, although both mechanisms coexist in the parietal cells of the gastric mucosa. Thus, during the application of (131)I for imaging or for the treatment of DTC patients, except for the short period of time immediately after the oral administration, when the radionuclide passes through the stomach, the concentration of (131)I in the gastrointestinal tract is due to its active accumulation and excretion by the gastric mucosa. PPI act only on the hydrochloric acid secretion not affecting the biologic properties of iodine.