In the 1970's, the efficacy of oral nitroglycerin therapy was seriously challenged, primarily on the basis of animal studies showing complete first-pass hepatic metabolism of nitroglycerin. Today, it is generally accepted that high oral doses of nitroglycerin do show antianginal efficacy. It has been suggested that this efficacy results from saturation of hepatic metabolism by the large oral doses administered, although the experimental evidence in humans purporting to support this may be questioned. In the present investigation, the bioavailability of oral nitroglycerin when administered in a capsule dosage form and as a solution was determined. Oral doses of nitroglycerin were less than 1% bioavailable. However, substantially high concentrations of the relatively low activity dinitrate metabolites were measured in plasma. We hypothesize that the activity of oral nitroglycerin preparations may result from high concentrations of the dinitrate metabolites, although this was not directly tested in the bioavailability studies described here.