We explored the association between social factors and adult periodontitis by comparing self-reported information for daily strains and symptoms of depression in 71 cases and 77 controls. Cases and controls were selected from among 1,426 participants in the Erie County Risk Factor Study. We found differences among those who scored higher than their peers on measures of social strain. The odds ratio (OR) and 95% confidence interval (95% CI) for the association between case status and Role Strain score of 2.27 or more was 2.84, 95% CI = 1.08 to 7.46. We also examined serum antibody, dichotomized at the median, for three periodontal pathogens (Bacteroides forsythus [IgG Bf], Porphyromonas gingivalis [IgG Pg], Actinobacillus actinomycetemcomitans [IgG Aa]), and assessed interaction between antibody levels and a Depression score derived from the Brief Symptom Inventory. IgG Pg and IgG Aa were both strongly associated with case status (OR = 4.52, 95% CI = 1.99 to 10.3 and OR = 5.29, 95% CI = 2.34 to 12.0, respectively). IgG Bf was associated with periodontal disease but only among individuals who had higher scores for Depression (OR = 6.75, 95% CI = 1.25 to 36.5). Smoking status was associated with case status (OR = 4.95, 95% CI = 1.86 to 13.2). We assessed these findings prospectively by examining factors associated with more extensive disease among the 71 case subjects after 1 year of follow-up. We found baseline smoking status and IgG Bf among individuals scoring high on Depression at baseline to be associated with more extensive disease (8.1% or more of the sites showing further breakdown). In this population an elevated Depression score may be a marker for social isolation, which could play a role in immune function during periods of social strain. This exploratory analysis has served to identify specific lines of inquiry concerning psychosocial measures as important environmental factors in adult periodontitis.