Accurate sequence alignments of distantly related proteins are crucial for the better understanding of proteins at their family/superfamily level. However, such alignments of distantly related proteins are often hard to obtain by automatic multiple sequence alignment programs. Hence, we suggest a protocol that permits the reliable sequence alignment of distantly related proteins whose structural information is available. This protocol employs two stages of structure-based sequence alignments in order to obtain reliable alignments. The method proposed is clearly suited to work for protein structural members with distant relationships. We further propose a novel assessment of the derived alignments using the measurements of the structural variations and the percentage secondary structural equivalences. This structure-based sequence alignment protocol can be employed for a single superfamily or for a large number of structural domain superfamilies in a near-automatic and rapid manner.