This work compared the effect of challenge with Vibrio tapetis, the etiologic agent of brown ring disease (BRD) in clams, and other bacterial strains on defense-related factors in four bivalve species: Ruditapes philippinarum (highly susceptible to BRD), R. decussatus (slightly susceptible to BRD), Mercenaria mercenaria and Crassostrea virginica (both non-susceptible to BRD). Results show that bacterial challenge modulated defense-related factors, namely total and differential haemocyte counts, percentage fo viable haemocytes, and lysozyme activity, both in haemolymph and extrapallial fluid. Injection with bacteria induced a response that was dependent upon the bacterial and bivalve species investigated, and upon the site on inoculation: external (pallial cavity), pseudo-internal (extrapallial space), or internal compartment (adductor muscle). The most conspicuous changes were systematically measured in R. phillipinarum injected with V. tapetis, indicating a bacterial pathogenicity particular to the host in which it causes a specific disease syndrome. Alterations of defense-related factors were maximal in haemolymph of clams injected with V. tapetis in the muscle, and in the extrapallial fluid when the bacteria were injected into the pallial or the extrapallial cavity. Resistance to the development of the BRD symptom was not related to the extent of the haemocyte reaction measured following in vivo challenge.