The molecular mechanisms responsible for protein structural changes in the central nervous system leading to Alzheimer's disease are unknown, but there is evidence that a family of proteins known as septins may be involved. Septins are a conserved group of GTP-binding proteins which participate in various cellular processes, including polarity determination and membrane dynamics. SEPT1, SEPT4, and SEPT2 have been found in deposits known as neurofibrillary tangles and glial fibrils in Alzheimer's disease. In this study, we provide molecular-level information for the interaction of SEPT2 with Langmuir monolayers at the air/water interface, which are used as simplified membrane models. The high surface activity of SEPT2 causes it to adsorb onto distinct types of lipid Langmuir monolayers, namely dipalmitoylphosphatidylcholine and PtdIns(4,5)P2. However, the interaction with PtdIns(4,5)P2 is much stronger, not only leading to a higher adsorption, but also to SEPT2 remaining inserted within the membrane at high surface pressures. Most importantly, in situ polarization-modulated infrared reflection absorption spectroscopy results indicated that the native secondary structure of SEPT2 is preserved upon interacting with PtdIns(4,5)P2, but not when dipalmitoylphosphatidylcholine is at the air/water interface. Taken together, the results presented here suggest that the interaction between SEPT2 and the cell membrane may play an important role in the assembly of SEPT2 into amyloid-like fibers.