Structural irregularity is a crucial issue in assessing seismic vulnerability of both new and existing buildings. European technical codes provide simple criteria to define irregularities in plan and in elevation, amplifying the seismic actions and/or introducing torsional effects. Nevertheless, this approach only considers geometrical irregularity. For existing buildings, another source of irregularity comes from the non-uniform distribution of the material strength. In particular, for existing reinforced concrete (r.c.) structures, it is possible to detect significant spread of the concrete compressive strength not only from different structural elements but also from different parts of the same member. In this work, non-linear static analysis is performed on two case-studies of r.c. buildings characterized by geometrical and mechanical irregularity. The resistance of each column is determined with an extensive experimental campaign with in situ and laboratory test (about 600 in situ tests). The results are analyzed considering both local and global effects in terms of resistance of the single elements and of the entire buildings. In this sense, shear and bending failure mechanism are taken into account. The effect of story flexibility is also considered in the models. Fragility curves are calculated for the buildings with random distribution of the compressive strength of the columns. The results are then compared with the approaches proposed by the Eurocodes evaluating in the standard approach proposed by technical codes is conservative or not.