AbstractHistorical masonry structures have a great interest in civil engineering because they constitute a large part of the world’s building heritage. In this paper, the effects that different geometrical (panel ratio, block ratio, and bond type) and mechanical (friction ratio) parameters have on the in-plane structural response of brick masonry panels are investigated. A discrete modeling approach, based on a limit analysis and capable of reproducing sliding mechanisms, formulation by one of the authors has been adopted, enhanced, and implemented. Results, in terms of collapse multipliers and collapse mechanisms, are presented and analyzed following a systematic statistical approach. Statistically significant effects have been found for each factor considered. Furthermore, the statistical model adopted included nonlinear terms that allowed the identification of whether the effect of one parameter on the response depends on the level of any other parameters. Thus, it was observed that two-way factor interactions played an important role in the in-plane response of masonry panels. The panel ratio-friction ratio two-way factor interaction was the one with a more significant effect.