The reactivity of Pd4, Pt4, Cu4, Ag4, and Au4 clusters supported on TiC(001) toward molecular hydrogen dissociation has been studied by means of density functional based theory and periodic models and compared to that of the (111) and (001) surfaces. Pd4 and Pt4 interact rather strongly with the TiC(001) substrate, but the interaction of molecular hydrogen with the Pd4/TiC and Pt4/TiC systems is also very strong. As a consequence of the substantial admetal↔carbide interactions, the adsorbed H2 molecule becomes more difficult to dissociate than on the corresponding extended (111) and (001) surfaces. Here, having a small supported particle does not lead to an enhanced chemical activity. On the contrary, for the Cu4/TiC, Ag4/TiC, and Au4/TiC systems the combination of the small size of the particle and the polarization induced by the underlying carbide facilitates the dissociation of the hydrogen molecule with respect to the case of the extended surfaces. Here, the reduced size effectively enhances the activity of the supported particle. Thus, our results for the M(111), M(100), and M4/TiC(001) systems show the complex interplay that can take place among the nature of the admetal, particle size effects, and support interactions.