One approach that can address these drawbacks is surface-enhanced infrared absorption (SEIRA) spectroscopy combined with tethered bilayer lipid membranes (tBLMs). Infrared (IR) spectroscopy is used routinely for mechanistic protein studies providing rich information ranging from large secondary structural reorganization to subtle changes in electrostatic environments. In SEIRA spectroscopy, a nanostructured Au film further amplifies this information in a surface-sensitive way. Accordingly, based on a plasmonic mechanism, IR signals of molecules within 10 nm to the Au surface are enhanced 10 2 -10 3 times, lowering the detection limit to the femtomole range. In addition, the Au film serves as a support to tether the tBLM to the surface-enhancing 10 nm-region (Figure ). This provides the unique advantage of selectively monitoring processes at the membrane interface as demonstrated in functional 2 studies of membrane proteins or membrane-active peptides. This is in contrast to alternatives like attenuated total reflection IR (ATR-IR) spectroscopy, which is characterized by a penetration depth of ≥1 μm, therefore detecting interfacial and bulk processes simultaneously. In this work, we demonstrate the combination of SEIRA and tBLMs as a tool for the label-free detection of viral binding and fusion events using the Influenza A virus (IAV; X31 strain) as model system. As an enveloped virus, IAV contains an outer membrane, which houses, among others, the hemagglutinin (HA) glycoprotein. This protein binds to sialic acids as specific attachment factors in the host membrane and catalyzes virusmembrane fusion. We successfully detect the vibrational fingerprint of the segments of HA as they interact specifically with the tBLM, the latter playing the role of the host membrane. Furthermore, triggering IAV membrane fusion via pH change, we observe relevant viral peptide/membrane interactions and potential lipid mixing events between the virus and the host membrane.