Meloxicam, a nonsteroidal anti-inflammatory drug (NSAID), is known as a selective cyclooxygenase-2 inhibitor. Cyclooxygenase-2 is a membrane protein, functionally coupled to an interfacial enzyme, phospholipase A2. Consequently, it may be supposed that the interactions of NSAIDs with lipid membranes play a role in the anti-inflammatory process. In order to investigate the mechanism of this process, Langmuir films formed with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, or 1,2-myristoyl-sn-glycero-3-phosphoethanolamine were exposed to meloxicam and its beta-cyclodextrin inclusion complex. The monolayers were studied by measuring surface pressure, electric surface potential, Brewster angle micrographs, polarization-modulation infrared reflection-absorption spectra, and phospholipase A2 activity; the inclusion complex was studied using molecular modeling. The results obtained show that the monolayers formed in the presence of meloxicam and its complex are expanded and more liquid-like compared to pure lipids. Both compounds modify hydration of the lipid polar heads, orientation of the molecules, morphology of the domains, and the rate of lipolysis catalyzed by phospholipase A2. The latter effect may be involved in the anti-inflammatory activity of meloxicam. Importantly, the effects observed with the meloxicam-beta-cyclodextrin complex are more pronounced compared to those of the free meloxicam. This observation may be relevant for developing new meloxicam preparations with increased bioavailability.