Accurate prediction of the domain content and arrangement in multi-domain proteins (which make up >65% of the large-scale protein databases) provides a valuable tool for function prediction, comparative genomics and studies of molecular evolution. However, scanning a multi-domain protein against a database of domain sequence profiles can often produce conflicting and overlapping matches. We have developed a novel method that employs heaviest weighted clique-finding (HCF), which we show significantly outperforms standard published approaches based on successively assigning the best non-overlapping match (Best Match Cascade, BMC).