1 Unexpectedly low plasma concentrations of mexiletine were observed in three patients treated with mexiletine and concurrently taking phenytoin. 2 Six healthy volunteers were given a single oral dose of mexiletine (400 mg), before and after 1 week of phenytoin administration (300 mg/day). 3 The mean +/‐ s.d. area under the plasma mexiletine concentration‐time curve decreased from 17.67 +/‐ 6.21 to 8.01 +/‐ 3.64 micrograms ml‐1 h (P less than 0.003). 4 The mean +/‐ s.d. half‐life of elimination of mexiletine decreased from 17.2 +/‐ 5.26 to 8.4 +/‐ 4.17 h (P less than 0.02) 5 The suggested mechanism of the interaction is hepatic mixed‐function oxidase enzyme induction by phenytoin. 6 The interaction is likely to be clinically significant.