Objectives. We take a biopsychosocial perspective on age-related diseases by examining psychological correlates of having multiple chronic conditions and determining whether positive psychological functioning predicts advantageous profiles of biological risk factors. Method. Respondents to the national survey of Midlife in the United States who participated in clinical assessments of health and biological processes (n = 998) provided information on chronic medical conditions and multiple domains of psychological functioning. Serum concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP) were determined from fasting blood samples. Results. Life satisfaction declined with increasing comorbidity while negative affect increased. In contrast, positive affect, purpose in life, and positive relations with others were unrelated to comorbidity status. Significant interactions showed that although IL-6 and CRP increased with increasing number of chronic conditions, respondents with higher levels of purpose in life, positive relations with others, and (in the case of CRP) positive affect had lower levels of inflammation compared with those with lower well-being scores. Discussion. The results suggest that many older adults with medical comorbidities maintain high levels of positive psychological functioning that are in turn linked to better profiles of biological disease risk.