Salivary host-defence peptides include defensins, histatins and cathelicidin. We have investigated the effects of these peptides on the microbial composition of dental plaques. Salivary consortia, established within hydroxyapatite disc models, were exposed during development to physiological levels of human neutrophil proteins (HNP) 1 and 2; human β defensins (hβD) 1, 2 and 3; histatins (His) 5 and 8; and cathelicidin (LL37). Effects on aggregation and microbial composition were determined using fluorescence microscopy; and differential culture with PCR-DGGE, respectively. LIVE/DEAD microscopic analysis indicated that HDPs decreased total bacterial viability, whilst β defensins, paired HNPs, His 5, His 8 and the HDPs combined inhibited bacterial aggregation. According to differential culture, all test HDPs (except His 5) significantly decreased the abundance of Gram-negative anaerobes and lactobacilli (except HNP 2, hβD 1, paired HNPs and His 5). Combined HNPs and paired hβD 1 and 3 inhibited streptococci, whereas HNP 1, hβD 1, hβD 3, His 5 and LL37 increased streptococcal numbers. According to cluster analyses of DGGE profiles, HDP-exposed plaques were compositionally distinct from undosed controls. Thus, whilst HDPs reportedly exhibit variable potency against oral bacteria in endpoint susceptibly tests, exposure of nascent plaques can markedly influence bacterial viability, composition and microbial aggregation.