Although considerable work is being carried out with pyridoxalated glutaraldehyde-stabilized stroma-free hemoglobin solution (SFHS-pp) as a possible blood substitute, it is not known whether the SFHS-pp has any adverse effect on some aspects of reticuloendothelial (RE) function. To determine this, 131I-gelatinized trioleate (GT) was injected 30 min or 3 days after the injection of 45 or 100 mg/100 gm BW SFHS-pp (low and high dose, respectively). The results indicate that low as well as high dose SFHS-pp significantly decreased splenic uptake and transiently increased pulmonary uptake of GT. Hepatic retention of GT, however, increased 3 days following SFHS-pp administration, indicating that there was a stimulation of this aspect of liver RE function at that time. The intravascular clearance rates of GT at 3 days were also markedly faster, but no dose effect relationship was seen. This suggests that there was an overall stimulation of RE function 3 days following SFHS-pp administration. These results provide support for the safety of polymerized stroma-free hemoglobin solution for use as an oxygen-carrying volume support.