Antigen-combining sites of antibodies are constructed from six loops from VL and VH domains. The third hypervariable region of the heavy chain is far more variable than the others in length, sequence and structure, and was not included in the canonical-structure description of the conformational repertoire of the three hypervariable regions of V kappa chains and the first two of VH chains. Here we present an analysis of the conformations of the third hypervariable region of VH domains (the H3 regions) in antibodies of known structure. We define the H3 region as comprising the residues between 92Cys and 104Gly. We divide it into a torso comprising residues proximal to the framework, four residues from the N terminus and six residues from the C terminus, and a head. There are two major classes of H3 structures that have more than ten residues between 92Cys and 104Gly: (1) the conformation of the torso has a beta-bulge at residue 101, and (2) the torso does not contain a bulge, but continues the regular hydrogen-bonding pattern of the beta-sheet hairpin. The choice of bulged versus non-bulged torso conformation is dictated primarily by the sequence, through the formation of a salt bridge between the side-chains of an Arg or Lys at position 94 and an Asp at position 101. Thus the torso region appears to have a limited repertoire of conformations, as in the canonical structure model of other antigen-binding loops. The heads or apices of the loops have a very wide variety of conformations. In shorter H3 regions, and in those containing the non-bulged torso conformation, the heads follow the rules relating sequence to structure in short hairpins. We surveyed the heads of longer H3 regions, finding that those with bulged torsos present many very different conformations of the head. We recognize that H3, unlike the other five antigen-binding loops, has a conformation that depends strongly on the environment, and we have analysed the interactions of H3 with residues elsewhere in the VH domain, in the VL domain, and with ligands, and their effects on the conformation of H3. We tested these results by attempts to predict the conformations of H3 regions in antibody structures solved after the results were derived. The general conclusion of this work is that the conformation of H3 shows some regularities, from which rules relating sequence to conformation can be stated, but to a less complete degree than for the other five antigen-binding loops. Accurate prediction of the torso conformation is possible in most cases; predictions of the conformation of the head is possible in some cases. However, our understanding of the sequence-structure relationships has reduced the uncertainty to no more than a few residues at the apex of the H3 region.