Nitroglycerin is rapidly lost from solution when incubated with red blood cells or whole blood. The assumption that the loss is enzymatic in nature may not be true, since no major metabolite is detected during this incubation. Explanation on the basis of a chemical reaction is also difficult, since the products of the chemical hydrolysis of nitroglycerin are the same as the metabolic products. After an initial rapid loss, nitroglycerin disappearance at 37 degrees follows an apparent first-order process in the concentration range of 10--480 ng/ml when incubated with washed red blood cells suspended in normal saline solution. The half-life for the reaction of the apparent first-order phase varies with the initial concentration and increases as the concentration increases (4 min at 10 ng/ml, 52 min at 480 ng/ml), suggesting a mixed kinetic mechanism. Metabolites of nitroglycerin (1,2- and 1,3-dinitroglycerin) react similarly to nitroglycerin in terms of an apparent initial, fast step, a secondary first-order dependence, and concentration-dependent rate effects; however, the rate of the reaction is much slower (t 1/2 = 33 min at 10 ng/ml) for the metabolite. These data suggest the possibility of a physical mechanism for the loss of nitroglycerin. Since the loss to red blood cells can be rapid, it seems that the mechanism should be delineated, and that the rate of disappearance be considered in an analysis of the pharmacodynamics of the drug.