1 The effects of diphenhydramine on the buccal absorption, in vivo absorption and the in vitro dissolution of methaqualone have been studied. 2 Diphenhydramine significantly reduced the buccal absorption of methaqualone and the effect was dose and pH dependent. In vivo, diphenhydramine did not alter the rate of absorption or the distribution of methaqualone in blood. In vitro, the presence of diphenhydramine increased the rate of dissolution of methaqualone and the effect was more marked when the particle size was small. 3 The reasons for and the implications of these apparently contradictory results are discussed and it is concluded that any increased efficacy resulting from combining diphenhydramine with methaqualone cannot be due to increased plasma drug levels.