Flexible multi-generation systems (FMGs) consist of integrated and flexibly operated facilities that provide multiple links between the different sectors of the energy system. The present study treated the design optimization of a conceptual FMG which integrated a methanol-producing biorefinery with an existing combined heat and power (CHP) unit and industrial energy utility supply in the Danish city of Horsens. The objective was to optimize economic performance and minimize total CO2 emission of the FMG while it was required to meet the local district heating demand plus the thermal utility demand of the butchery. The design optimization considered: Selection, dimensioning, location and integration of processes; operation optimization with respect to both hourly variations in Operating conditions over the year as well as expected long term energy system development; and uncertainty analysis considering both investment costs and operating conditions. Applying a previously developed FMG design methodology, scalable models of the considered processes were developed and the system design was optimized with respect to hourly operation over the period 2015-2035. The optimal design with respect to both economic and environmental performance involved a maximum-sized biorefinery located next to local industry rather than in connection with the existing CHP unit. As the local industry energy demands were limited when compared to the biorefinery dimensions considered, process integration synergies were found to be marginal when compared to the economic and environmental impact of the biorefinery for the present case. Assessing the impact of uncertainties on the estimated FMG performances, the net present value (NPV) of the optimal design was estimated to vary within the range 252.5-1471.6 ME in response to changes of 25% in investment costs and methanol price, and considering two different electricity price scenarios. In addition, a change in the interest rate from 5% to 20% was found to reduce the lower bound of the NPV to 181.3 ME for reference operating conditions. The results suggest that the applied interest rate and operating conditions, in particular the methanol price, would have a much higher impact on the economic performance of the designs than corresponding uncertainties in investment costs. In addition, the study outcomes emphasize the importance of including systematic uncertainty analysis in the design optimization of FMG concepts. (C) 2016 Elsevier Ltd. All rights reserved.