Nuclear medicine technology assumes responsibility for examinationspecific patient preparation procedures. This requires a clear understanding of the possible effects of medications on the outcome of examinations. There is evidence that common over-the-counter drugs, histamine 1 (H1) and histamine 2 (H2) receptor blockers and proton pump inhibitors, may directly or indirectly affect thyroid function. The objective was to determine whether short-term use of these drugs alters biodistribution of radioiodine in a rat model. Methods: Rats received no drug (controls) or daily subcutaneous injections of H1 blocker (promethazine), H2 blocker (famotidine), or proton pump inhibitor (esomeprazole) commencing 1 d before a single intraperitoneal injection of 0.037 MBq (1 μCi) of 131 I (NaI) and continuing daily until euthanasia at either 1 d or 8 d after 131 I. Organ uptake of 131 I by control and drug-treated rats was compared by γ-well counting. Results: Promethazine significantly increased uptake of 131 I by the thyroid (drug-treated-to-control ratios) both at 1 d (1.32) and 8 d (1.52) after 131 I. Both famotidine and promethazine (respectively) significantly increased salivary gland uptake of 131 I (drug-treated-to-control ratios) at 1 d (1.37, 1.40) and 8 d (4.52, 5.57) after 131 I. Promethazine significantly increased gastric 131 I uptake (drug-treated-to-control ratios) at 1 d (1.47) and 8 d (1.46) after 131 I. Famotidine and promethazine (respectively) significantly decreased uptake of 131 I by the liver (drug-treated-to-control ratios) at 1 d (0.60, 0.71) after 131 I but resulted in a marked increase over control levels (11.21, 9.28) at 8 d. Blood levels of 131 I were not altered by drug treatment. Esomeprazole did not affect radioiodine distribution. Conclusion: H1 and H2 blockers alter the biodistribution of radioiodine in the rat. Although the findings remain to be confirmed in humans, these drugs could increase radiation exposure to nontarget tissues, particularly the stomach and salivary tissue, during 131 I therapy and consideration should be given toward avoiding the elective use of these drugs during radioiodine therapy.