This work utilized PRINT (particle replication in non-wetting templates) technology to fabricate extremely soft, biologically inspired hydrogel particles that mimicked the size, shape and modulus of red blood cells (RBCs). Hemoglobin, the oxygen carrying protein in RBCs, was conjugated into these microparticles without adverse effect on the structure and function of the protein. A prior modification on surface of PRINT particles followed by hemoglobin conjugation enabled the protein-laden microparticles to circulate in blood. The results of this study can potentially lead to a RBC substitute for blood transfusion without causing vasoconstriction, a major hurdle often seen in other hemoglobin-based oxygen carriers (HBOCs). Vasoconstriction is believed to be inversely proportional to the size of the HBOC. Microparticles with size around or larger than 1 μm may be appropriate as hemoglobin carriers to minimize vasoconstriction, yet they generally do not circulate well in blood vessels due to filtration by small capillaries. Our previous study demonstrated that microparticles with a diameter of 6 μm could still circulate a long time in blood when they were made to be deformable enough. Retaining the same low modulus, hydrogel particles with diameters ranging from 0.8 to 8.9 μm were studied on their pharmacokinetics and biodistribution in mice. The particles mimicking size of RBCs demonstrated longer circulation times, hence were used as carriers for hemoglobin in this study. Bovine hemoglobin could be conjugated to the RBC mimicking particles (RBCMs) through reaction between carboxyl groups in the particles and amine groups on hemoglobin. However, hemoglobin distributed on the surface of the RBCMs made them tend to aggregate in blood and more recognizable by macrophages, resulting in rapid removal from circulation. A strategy was used to synthesize blank RBCMs with such an asymmetric distribution of carboxyl groups that most of them were in the interior with limited exposure on the exterior. After conjugation, hemoglobin could be predominantly confined in the interior of the particles with a neutral surface charge. These particles could circulate in blood with much lower accumulation in the lung than the counterparts with hemoglobin on their surface.