This work focuses on the application of different biophysical techniques to study the interaction of tolmetin with membrane mimetic models of different dimensionality (liposomes, monolayers, and supported lipid bilayers) composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), used as a representative phospholipid of natural membranes. Several biophysical techniques were employed: Fluorescence steady-state anisotropy to study the effects of NSAIDs on membrane microviscosity and thus to assess the main phase transition of DPPC, surface pressure-area isotherms to evaluate the adsorption and/or penetration of NSAIDs into the membrane, IRRAS to acquire structural information of the lipid membrane upon interaction with the drugs, and AFM to study the dynamic change in surface topography of the lipid bilayers caused by interaction with tolmetin. The experiments were performed taking into account the physiological conditions that tolmetin may find in the course of its in vivo therapeutic activity. Therefore, the studies covered the interactions of tolmetin with lipid membranes in both gel and liquid-crystalline phases at two pH conditions: 7.4 (plasma pH) and 5 (inflamed tissue pH). The applied models and techniques provided detailed information about different aspects of the tolmetin-membrane interaction. The studies have shown that tolmetin-membrane interaction is strongly dependent on the degree of drug ionization and of the lipid phase state, which can be related with the therapeutic action and gastro intestinal toxicity of this drug.