The results of an experimental and numerical investigation on the mechanical response of undamaged and damaged 2-ply Laminated Glass (LG) plates with different interlayers are presented in the paper. Three different interlayers, polyvinyl butyral (PVB), SentryGlas (SG) and Saflex DG41 (DG41) characterized by different rheological properties and fully tempered glass plates were considered. Simply supported plates under out of plane loads were tested in three different configurations: configuration 0, undamaged; configuration I, partially damaged, with a broken ply below (bottom ply) and configuration II, partially damaged, with a broken ply above (top ply). In the three configurations the top ply is always subjected to compression while the bottom one is in tension. The main aspects and the different response of each configuration were discussed and compared. Experimental results highlighted the influence of the interlayer properties on both the pre- and post-breakage behavior. Moreover, numerical models were developed to reproduce the experimental results. For the post-breakage response two different strategies were developed: a) the equivalent temperature variation and b) elastic-brittle constitutive law. Differences and advantages associated with both solutions are discussed. Finally, extensive parametric numerical analyses are proposed to underline the influence on the mechanical response of different parameters: i) plate geometry (size effect); ii) interlayer thickness; iii) glass thickness; iv) additional glass ply (3-ply LG plate). It is underlined that the size effect plays an important role on the mechanical response of LG plates and it should be always considered in the design. The numerical findings were used to define a critical length from which the plates behave as monolithic, independently of the stiffness of the interlayer.