When dealing with seismic reliability assessment of structural systems, many uncertainty sources have to be handled by the risk analyst, who is asked to make some reasonable assumptions in order to carry out his/her seismic safety quantification. Indeed, slight changes in the definition of input parameters and/or the use of different empirical or analytical models can strongly impact the final reliability outcomes. The present work aims therefore to first analyse this issue clearly highlighting all possible sources of uncertainties that an analyst must face with, and then investigate their impact on the final reliability index variability via the use of a case-study represented by an existing multi-span steel-concrete composite bridge to better understand which of these sources is more impacting on the final estimates.