Activated factor VII (FVIIa) is a trypsin-like serine protease that plays a key role in the initiation of the blood coagulation cascade. FVIIa, which comprises a light chain (152 residues) and a heavy chain (254 residues) linked by a disulphide bond, is generated by the cleavage of the Arg152-Ile153 peptide bond in factor (F)VII. While a corresponding internal peptide bond cleavage unleashes the activity of other trypsin-like enzymes, FVIIa is unusual in that it remains in a zymogen-like state after cleavage and only becomes an efficient catalyst when associated with tissue factor, its protein cofactor and allosteric regulator. We have determined the structure of free FVIIa lacking the gamma-carboxyglutamic acid (Gla) domain as a means to elucidate the molecular reasons for its poor activity when not bound to tissue factor and the conformational changes induced by its association with tissue factor.