Dextrans show great promise for delivery of therapeutic agents. Dextran acetates (DAs) were synthesized with increasing degrees of substitution (DA1 < DA2 < DA3) by the reaction of the polysaccharide dextran (70 kDa) with acetic anhydride. A series of polyethylene glycol (PEG)/DA microspheres were prepared and tested with bovine serum albumin (BSA) functioning as a model protein. Particle size (0.74–0.85 μm) and encapsulation efficiency (56–70%) increased with the degree of substitution along with a slower release rate of protein from PEG/DA microspheres. Time to release 90% of protein rose from 31 to 118 min. Percentage of BSA released from PEG and PEG/DA3 microspheres with time (min) was modeled mathematically [YPEG = 100(1 − e−0.12t); YPEG/DA3 = 100(1 − e−0.024t)] to predict cumulative delivery from mixtures in vitro over a period of hours when constrained to a target level at 30 min. The system is examined for potential application in thrombolytic therapy. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 2699–2705, 2013.