Background: A molecular epidemiologic study provided the opportunity to characterize the biology of the biofilm–gingival interface (BGI) in 6,768 community‐dwelling subjects.Methods: Disease classifications and multivariable models were developed using clinical, microbial, inflammatory, and host‐response data. The purpose was to identify new clinical categories that represented distinct biologic phenotypes based upon DNA checkerboard analyses of eight plaque bacteria, serum immunoglobulin G (IgG) titers to 17 bacteria, and the gingival crevicular fluid (GCF) levels of 16 inflammatory mediators. Five BGI clinical conditions were defined using probing depths (PDs) and bleeding on probing (BOP) scores. Subjects with all PDs ≤3 mm were grouped as BGI‐healthy (14.3% of sample) or BGI‐gingivitis (BGI‐G, 15.1%). Subjects with one or more PDs ≥4 mm [deep lesion (DL)] were divided into low BOP (18.0%), moderate BOP (BGI‐DL/MB, 39.7%), and severe BOP (BGI‐DL/SB, 12.9%).Results: Subjects with BGI‐G had increased levels of Campylobacter rectus–specific serum IgG levels (P = 0.01), and those with BGI‐DL/SB had increased IgG levels to Porphyromonas gingivalis (P < 0.0003) and C. rectus (P < 0.01). BGI‐DL/SB subjects had an excessive GCF interleukin (IL)‐1β and prostaglandin E2 response and an enhanced chronic inflammatory response with significant increases in GCF IL‐6 and monocyte chemotactic peptide‐1. Within BGI‐DL/SB subjects, more severe pocketing and BOP were associated with higher levels of GCF IL‐1β, not higher microbial counts or plaque scores.Conclusions: New BGI classifications create categories with distinct biologic phenotypes. The increased titers of C. rectus IgG among 68.5% of the BGI‐G subjects and elevated P. gingivalis titers among BGI‐DL/MB and BGI‐DL/SB subjects (63.8% and 75.7%, respectively) are strongly supportive of the microbial specificity of pathogenesis for BGI categories.