The degradation of solid oxide fuel cells (SOFC) depends on stack and system design and operation. A methodology to evaluate synergistically these aspects to achieve the lowest production cost of electricity has not yet been developed. A repeating unit model, with as degradation processes the decrease in ionic conductivity of the electrolyte, metallic interconnect corrosion, anode nickel particles coarsening and cathode chromium contamination, is used to investigate the impact of the operating conditions on the lifetime of an SOFC system. It predicts acceleration of the degradation due to the sequential activation of multiple processes. The requirements for the highest system efficiency at start and at long-term differ. Among the selected degradation processes, those on the cathode side here dominate. Simulations suggest that operation at lower system specific power and higher stack temperature can extend the lifetime by a factor up to 10, because the beneficial decrease in cathode overpotential prevails over the higher release of volatile chromium species, faster metallic interconnect corrosion and higher thermodynamic risks of zirconate formation, for maximum SRU temperature below 1150 K. The counter-flow configuration, combined with the beneficial effect of internal reforming on lowering the parasitic air blower consumption, similarly yields longer lifetime than co-flow. (C) 2012 Elsevier B.V. All rights reserved.