Ten healthy adult subjects took a single daily dose of phenytoin for 9 days to achieve a steady‐state serum phenytoin concentration in the therapeutic range. While continuing on phenytoin, subjects took increasing doses of salicylate in a step‐wise fashion, each dose (325, 650, and 975 mg) given every 4 hr for 48 hr. Serum (total) and salivary (free) phenytoin concentrations and serum salicylate concentrations were measured before and after each dose level of salicylate. Protein binding displacement of phenytoin by salicylate occurred only at the highest salicylate dose. Serum phenytoin control levels fell from 13.5 ± 1.2 to 10.3 ± 0.8 µg/ml (p<0.01), salivary phenytoin levels rose from 0.97 ± 0.09 to 1.13 ± 0.12 µg/ml (p<0.05), and phenytoin free fraction (salivary/serum ratio) increased from 7.14 ± 0.34% to 10.66 ± 0.57% (p<0.01) in the highest salicylate dose periods. There was no difference in these parameters during low‐dose or intermediate‐dose salicylate therapy. Linear‐regression analysis failed to show a relationship between serum salicylate concentration and serum or salivary phenytoin concentration. Although high‐dose salicylate induced protein binding displacement of phenytoin, it is unlikely that this is of clinical importance since the rise (16%) in the free (salivary) phenytoin concentration was small. Serum total phenytoin concentration may fall during salicylate therapy but the dose of phenytoin should not be altered unless there are overt signs of toxicity.Clinical Pharmacology and Therapeutics(1981)29,56–60; do