Blood substitutes, such as diaspirin cross-linked Hb (DBBF-Hb), have been considered for use during blood transfusions. Unfortunately, bolus injection of modified Hb has been shown to rapidly increase the leakage of microvessels to plasma albumin. This effect may result from production of excess reactive oxygen species (ROS) and could linked to the observed increase in degranulated mast cells (DMC). Disodium Cromoglycate (cromolyn) stabilizes mast cells and therefore might minimize the venular permeability in the rat mesentery. In ten anesthetized Sprague-Dawley rats, the mesenteric preparation was continuously suffused with cromolyn while the microvasculature was filled with DBBF-Hb solution (10 mg/ml) for 10 min. Six animals had received cromolyn pre-treatment (two intravascular injections over 30 min. (Experiment A)), and four had received pre-treatment with 2% HBS-BSA (Experiment B). Two more animals were pre-treated with HBS-BSA, without the DBBF-Hb infusion but with cromolyn suffusion (Experiment C). Another set of experiments was performed on five animals without cromolyn suffusion or any pre-treatment, but with DBBF-Hb infusion (Experiment D). All groups then received a 1-min perfusion of FITC-albumin, fixation for 60 min, and microscopic examination. Experiments A and B demonstrated a significant reduction in the number of venular leaks and DMC compared to experiment D, but not in the area of venular leaks. These results suggest mast cell degranulation is not a major contributor to microvascular leakage induced by DBBF-Hb.