Due to susceptibility of bridges in the past earthquakes, vulnerability assessment and strengthening of bridges has gained a particular significance. The objective of the present study is to employ an analytical method for the development of fragility curves, as well as to investigate the effect of strengthening on the RC box-girder bridges. Since fragility curves are used for pre-and post-earthquake planning, this paper has attempted to adopt the most reliable modeling assumptions in order to increase the reliability. Furthermore, to acknowledge the interaction of soil, abutment and pile, the effect of different strengthening methods, such as using steel jacketing and FRP layers, the effect of increase in the bridge pier diameter, and the effect of vertical component of earthquake on the vulnerability of bridges in this study, a three-span RC box-girder bridge was modeled in 9 different cases. Nonlinear dynamic analyses were carried out on the studied bridges subjected to 100 ground motion records via OpenSEES platform. Therefore, the fragility curves were plotted and compared in the four damage states. The results revealed that once the interaction of soil and abutment and the vertical component of the earthquake are accounted for in the calculations, the median fragility is reduced, implying that the bridge becomes more vulnerable. It was also confirmed that steel jackets and FRP layers are suitable methods for pier strengthening which reduces the vulnerability of the bridge.