Background We previously demonstrated that HBOC-201 is an efficient resuscitation fluid. However, little is known about its immunomodulatory effects. The goal of this study was to investigate human neutrophil activation after exposure to HBOC-201 and other low-volume resuscitation fluids. Methods Whole blood from 10 healthy volunteers was serially diluted with HBOC-201, 7.5% hypertonic saline (HTS), 7.5% hypertonic saline-6% dextran 70 (HSD), Hextend, or PentaLyte. After an incubation period, samples were analyzed for oxidative burst and CD11b expression using flow cytometry. Results Increases in both CD11b and oxidative burst activity were noted in samples diluted with HBOC-201, Hextend, PentaLyte, and lactated Ringer’s solution. Samples maximally diluted with HBOC-201 demonstrated increased CD11b expression when compared with lactated Ringer’s solution and Hextend (196.11% vs. 22.68% and 33.97%; p = 0.018 and p = 0.033). Conclusion Although differences were noted only at the highest dilutions, further studies investigating the effects of HBOC-201 are warranted. © 2003 Lippincott Williams and Wilkins, Inc.