Abstract Most papers in the literature address reliability analysis of isolated elements, like beams and columns. However, symmetry and regularity are often exploited in the construction of regular RC frames, resulting in the same or similar designs for all columns of a floor or all beams of a building. This leads to significant differences in member reliability, due to different axial load to bending moment ratios, in different parts of the structure. Moreover, load effects increase, and symmetry is lost under individual support settlements. In this scenario, reliability analyses are performed, for an intact 4-floors and 3-spans RC frame; and considering different settlement conditions. Monte Carlo simulation is performed, considering uncertainties in dead and live loading, and steel and concrete strengths. The results show that a settlement of 10 mm, corresponding to an angular distortion of 1/500, reduced the average reliability of the frame by only 14%, just the same, it reduced the reliability index of several cross-sections of the beams to up to 2.40, value lower than that recommended in the Model Code 2010. It is concluded that the methodology used in this work presents an important tool for the analysis of events not foreseen in the design, supporting the decision making about the need for intervention in the structures.