A variety of drugs which bind to iron have significant reductions in absorption when co-administered with iron compounds. The chemical structure of phenytoin indicates that there may be possible binding to iron ions. In vitro experiments were performed to determine whether any binding of iron to phenytoin occurred, and in vivo studies examined the effect of ferrous sulfate on phenytoin absorption in an isolated perfused rat jejunal model of drug absorption. The dose of phenytoin was limited by solubility and represents a human dose of 28 mg on a mg/kg basis for the rat assuming the total dose to be in 10 cm bowel in the rat. The ferrous sulfate doses were chosen to represent 28 and 300 mg doses on a similar basis to phenytoin. There was no significant effect of ferrous sulfate on phenytoin absorption or instability of phenytoin in the presence of ferrous sulfate in the rat. In vitro experiments indicated that little or no phenytoin binding to iron occurred. Results from animal model studies using low doses of phenytoin suggest it is unlikely that there will be a significant reduction in phenytoin absorption during concurrent therapy with iron salts.