Stress and depression may affect the onset and progression of periodontal disease. However, to the best of our knowledge, no published study has established whether the mechanisms by which stress and depression influence periodontal disease are physiologic, behavioral, or both. This cross-sectional pilot study explored the associations between psychologic factors, markers of periodontal disease, psychoneuroimmunologic variables, and behavior. This study included 45 periodontal patients referred by three dentists. Participants completed composite health, chronic stress, depression, and demographic questions, and salivary cortisol (CORT) was measured. A hygienist assessed the magnitude of periodontal disease. Stress, depression, and CORT were correlated with measures of periodontal disease. In addition, oral care neglect during periods of stress and depression was associated with attachment loss and missing teeth. After controlling for age, family history, and brushing frequency, depression and CORT were significant predictors of the number of missing teeth. A similar model also predicted the number of teeth with clinical attachment loss >5 mm. Stress and depression may be associated with periodontal destruction through behavioral and physiologic mechanisms. Addressing psychologic factors, such as depression, may be an important part of periodontal preventive maintenance.