The effect of iopamidol on the leptomeninges was tested and compared with that of metrizamide and normal saline solution in 18 dogs. Pathologic and clinical effects were evaluated at 24 hours and 14 days after cisternal injection of iopamidol, metrizamide, or normal saline solution. Pathologic changes were evaluated by microscopic examination of serial CSF samples and of sections of brain and spinal cord with the leptomeninges intact. Clinical changes were subjectively evaluated. Electromyograms and EEG were performed on each dog after physical and neurologic examination. There were no changes seen in neurologic status, electromyogram, or EEG in any of the dogs immediately after subarachnoid injection nor at 24 hours or 14 days later. Pathologic changes were limited to mild, moderate, or severe patchy hemorrhagic leptomeningitis seen at 24 hours after iopamidol or metrizamide was injected. The severity of changes were judged to be similar with both these agents. The CSF analysis and histologic evaluation of brain and spinal cord sections revealed a neutrophilic response to iopamidol and a mononuclear response to metrizamide. These findings indicate that iopamidol has minimal neurotoxicologic effect on the leptomeninges and therefore has merit as a myelographic agent.