Whooping cough is a re-emerging respiratory tract infection. It has become clear that there is a need for better understanding of protective immune responses and variation between Bordetella pertussis strains to aid the development of improved vaccines. In order to survive in the host, B. pertussis has evolved mechanisms to evade complement-mediated killing, including the ability to bind complement-regulatory proteins. Here we evaluate the variation in interactions with the complement system among recently isolated strains. Isolates whose genomes appear highly similar and cluster together on a SNP-based dendrogram were found to vary significantly in resistance to complement-mediated killing and in the deposition of C3b/iC3b, C5b-9 and C1 esterase inhibitor (C1-INH). The key role of Vag8 as a receptor for C1-INH was confirmed and its expression was shown to vary in a panel of isolates. A Vag8 knockout mutant showed increased sensitivity to complement-mediated killing. Antibodies in convalescent sera blocked C1-INH binding to B. pertussis and may play an important role in natural immunity.