Standardization of international health economic guidelines has been repeatedly requested. In this context, an international reference case was proposed, which constitutes an agreed approach for the key elements of health economic evaluation including study perspective, comparators, source of effectiveness data, role of modeling, main (economic) outcome, source of utilities, characterizing uncertainty. It is, however, questionable whether such a reference scenario can reasonably be applied across all health care systems. Our analysis pursues the question to which degree the Institute for Quality and Efficiency in Health Care's (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG) "General methods for evaluating the relation between cost and benefit" comply with the key elements of the reference case. In case of divergences, they will be described and discussed in light of the German social legislation and in consideration of current scientific evidence. In conclusion, the analysis revealed that IQWiG complied with the reference case in almost all aspects. Differences were found only with respect to the choice of main (economic) outcome and the source of utilities. These differences seem justified and well explained in the context of the German social legislation as well as in view of the weaknesses of the quality-adjusted life year (QALY) concept.