Using second-harmonic generation, we directly monitored adsorption of indomethacin, a nonsteroidal anti-inflammatory drug, to supported lipid bilayers composed of phospholipids of varying phase, cholesterol content, and head group charge without the use of extrinsic labels at therapeutically relevant aqueous concentrations. Indomethacin adsorbed to gel-phase lipids with a high binding affinity, suggesting that like other arylacetic acid-containing drugs, it preferentially interacts with ordered lipid domains. We discovered that adsorption of indomethacin to gel-phase phospholipids was endothermic and entropically driven, whereas adsorption to fluid-phase phospholipids was exothermic and enthalpically driven. As temperature increased from 19 to 34 degrees C, binding affinities to gel-phase lipids increased by 7-fold but relative surface concentration decreased to one-fifth of the original value. We also compared our results to the entropies reported for indomethacin adsorbed to surfactant micelles, which are used in drug delivery systems, and assert that adsorbed water molecules in the phospholipid bilayer may be buried deeper into the acyl chains and less accessible for disruption. The thermodynamic studies reported here provide mechanistic insight into indomethacin interactions with mammalian plasma membranes in the gastrointestinal tract and inform studies of drug delivery, where indomethacin is commonly used as a prototypical, hydrophobic small-molecule drug.