When used as release-controlling coating agents for tableted core-based pulsatile delivery systems, three different hydroxypropyl methylcellulose (HPMC) grades, Methocel E5, E50, and K4M, provided lag phases of varying duration (Methocel K4M > E50 > E5) and a prompt and quantitative model drug release. Dissolution/mechanical erosion, permeability increase and disruption of the hydrated polymeric layer were assumed to participate in the definition of the overall release pattern. Based on these premises, we investigated what process(es) might prevail in the release-controlling mechanism for each HPMC grade. The polymers were evaluated for dissolution and swelling, while the finished systems were concomitantly evaluated for drug release and polymer dissolution. The obtained results indicated likely similarities between Methocel E5 and E50 performances, which we hypothesized to be mainly dissolution/erosion-controlled, and a clearly different behavior for Methocel K4M. This polymer indeed proved to yield higher viscosity and slower dissolving gel layer, which was able to withstand extensive dissolution/erosion for periods that exceeded the observed lag phases. The particular characteristics of swollen Methocel K4M were shown to be associated with possible drug diffusion phenomena, which might impair the prompt and quantitative release phase that is typical of pulsatile delivery.