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Objectives: The study aims to identify and discuss the concept of the key assumption on which the indirect comparisons rely and to illustrate a practical approach to assure the validity. Methods: We firstly reviewed the theoretical background of the indirect comparisons and then suggested how the key assumptions can be assessed and accounted for using an example of common reference based indirect comparison. Results: The fundamental assumption behind the synthesized comparative effect obtained by indirect comparison is that the same effect would still be obtainable if it was directly measured in all of the trials that constitute the indirect comparison. An illustrative analysis demonstrated that conducting an indirect comparison without a meticulous assessment for the exchangeability could mislead the conclusion on the comparative effectiveness. Conclusions: Head-to-head trials could provide the most valid estimate of the comparative effect of a healthcare intervention. When competing interventions have not been evaluated in direct randomized trials or there is little available source by those trials, indirect comparisons may be utilized to provide an estimate of the comparative effect. However,the limitations also need to be highlighted, since the indirect comparison methodology relies upon certain important but conceptual and essentially unverifiable key assumption.