The extracellular domain of influenza A virus matrix protein 2 (M2, M2e) is conserved and is being evaluated as a quasi-universal influenza A vaccine candidate. We describe the crystal structure at 1.6 Å resolution of M2e in complex with the Fab fragment of an M2e-specific monoclonal antibody that protects against influenza A virus challenge. This antibody binds M2 expressed on the surface of cells infected with influenza A virus. Five out of six complementary determining regions interact with M2e, and three highly conserved M2e residues are critical for this interaction. In this complex, M2e adopts a compact U-shaped conformation stabilized in the centre by the highly conserved tryptophan residue in M2e. This is the first description of the three dimensional structure of M2e.