This is the first study of multiple applications of drug iontophoresis in the eye. We repeated ocular foscarnet iontophoresis in 10 eyes of 10 rabbits every third day at the same paralimbal site for a total of seven applications over a period of 21 days to determine the efficacy and toxicity of multiple applications of ocular foscarnet iontophoresis. Mean vitreous human foscarnet concentration of 189 +/- 50.6 microM (SD) was achieved four hours after the seventh consecutive iontophoretic application over a period of twenty-one days. These levels were within the therapeutic range (25-800 microM) for the treatment of CMV retinitis and comparable to the intravitreal foscarnet concentrations achieved in eyes treated with a only a single application of ocular iontophoresis. Electroretinography (ERG) and Slit-lamp biomicroscopy responses revealed no evidence of ocular toxicity. Indirect ophthalmoscopy of the retinas and gross examinations of the calottes revealed a single, small burn in the retina and choroid corresponding to the application site of the iontophoresis probe similar to the lesion resulting from a single application of iontophoresis. Light and electron microscopy revealed local tissue injury and fibrosis at the iontophoresis site, but adjacent areas were unaffected.