Mixed building frames constructed by reinforced concrete (r/c) in lower stories and structural steel in upper stories have been met with great scientifical interest as a common and often constructed building type. However, current seismic regulations do not provide special guidelines for the aforementioned vertically mixed building type, but only for building frames constructed with the same material throughout. In addition, a small number of respective literature works can be found, thus underlying the need for a thorough examination of the nonlinear behavior of mixed reinforced concrete—steel frames exposed to strong earthquakes. Mixed r/c-steel 3D frames were subject to non-linear time history analysis under selected strong earthquakes, considering appropriate nonlinear mechanical models for structural elements. Nonlinear response results were compared for two considered connection types of the steel part on the r/c part, which are called here as “fixed” and “fixed-pinned” connections. In this way, the nonlinear response of mixed frames is studied under extreme ground motions, towards the utmost unfavorable conditions. Selected comparative nonlinear response results and plots are presented to estimate the behavior of mixed frames. Qualitative remarks arise from the current described investigation leading to practical remarks for improving the design of mixed buildings that are available for the upgrade of current codes.