The concepts of the biorefinery and microgrid have emerged as ways to increase the sustainability of the energy infrastructure. Although typically considered as separate systems, synergies exist between the biorefinery and the microgrid, suggesting that a combined system could be more efficient than the individual systems. This paper explores this hypothesis by comparing the optimal designs and costs of the individual, and the combined biorefinery and microgrid systems. A novel design optimization problem considering synergistic operation of the biorefinery and microgrid is presented. A solution method to this problem is developed that exploits the separable nature of the optimization of such a "system of systems." Base case results show that the combined system costs are higher than those of the individual systems. However, by implementing a hydrogen recycle, significant savings are seen in the combined system, highlighting a direct advantage of system synergy. The effects of energy autonomy on the system are also analyzed and discussed. The overall analysis shows that the synergies between the biorefinery and microgrid can be exploited to create an energy system that is less costly and more efficient than the sum of its constituent parts. (C) 2016 Elsevier Ltd. All rights reserved.