The study concerned the effects of lidocaine and mepivacaine on rat mast cell histamine release. At low concentrations these drugs inhibited the histamine release induced by concanavalin A and compound 48/80 although, at high concentrations, they caused cell lysis. The mechanism of their inhibition of histamine release was studied by examining the pH dependence of the inhibitory action. In the absence of drugs, the release of histamine was not affected by the pH of the medium, but the inhibitory effects of the drugs increased with increase in pH. The percent inhibition of histamine release by these drugs at each pH was plotted against the calculated concentration of the nonionized form of the drug, according to the Henderson-Hasselbalch equation. The inhibitory action was correlated with the concentration of nonionized molecules, which readily penetrate the cell membrane. From the interaction of lidocaine with the phospholipid bilayer, it was concluded that this drug penetrates the lipid bilayer and that this effect increases with increasing pH of the medium. Thus, it seems that it is the nonionized form of local anesthetics that inhibits histamine release and that it is nonionized molecules that penetrate the mast cell membrane.