Decreased nitric oxide (NO) bioavailability is associated with a number of pathological conditions. Administration of a supplemental source of NO can counter the pathological effects arising from decreased NO bioavailability. A class of NO/nucleophile adducts that spontaneously release NO (NONOates) has been developed and its members show promise as therapeutic sources of NO. Because the NONOates release NO spontaneously, a significant portion of the NO may be consumed by the hemoglobin present in red blood cells (RBCs). Here we develop a model to analyze the efficacy of NO delivery, by membrane-impermeable NONOates, in the resistance arterioles. In the course of model development, we explore the impact of modeling RBCs in the blood stream as discrete 3-D particles or as a continuum. We find that the continuum model does not capture all of the features present in the particle model. Due to the computational complexity of the 3-D model, we assess the feasibility of reducing the model to a less intense 2-D configuration. We find that it is possible to represent the 3-D model with a 2-D model, if the RBC particles in the two models have the same surface area to volume ratios. Our model identified three features of blood vessels that will enhance NONOate efficacy: 1) the amount of NO delivered to the abluminal region increases with lumen radius; 2) the presence of a flow-induced RBC-free zone will augment NO delivery; and 3) extravasation of the NONOate into the insterstitial space will increase abluminal NO delivery. These results suggest that NONOates may be more effective in larger vessels and that NONOate efficacy can be altered by modifying permeability to the interstitial space.