BACKGROUND: Preoperative pain and depression predispose patients to delirium. Our goal was to determine whether pain and depressive symptoms interact to increase delirium risk. METHODS: We enrolled 459 persons without dementia aged > /=70 years scheduled for elective orthopedic surgery. At baseline, participants reported their worst and average pain within seven days and current pain on a 0-10 scale. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale and chart. Delirium was assessed with the Confusion Assessment Method and chart. We examined the relationship between preoperative pain, depressive symptoms and delirium using multivariable analysis of pain and delirium stratified by presence of depressive symptoms. FINDINGS: Delirium, occurring in 23% of the sample, was significantly higher in those with depressive symptoms at baseline than those without (relative risk, RR, 1.6, 95% confidence interval, CI, 1.2-2.3). Preoperative pain was associated with an increased adjusted risk for delirium across all pain measures (RR from 1.07-1.08 per point of pain). In stratified analyses, patients with depressive symptoms had a 21% increased risk for delirium for each one-point increase in worst pain score, demonstrating a significant interaction (P=0.049). Similarly, a significant 13% increased risk for delirium was demonstrated for a one-point increase in average pain score, but the interaction did not achieve statistical significance. INTERPRETATION: Preoperative pain and depressive symptoms demonstrated increased risk for delirium independently and with substantial interaction, suggesting a cumulative impact. Thus, pain and depression are vulnerability factors for delirium that should be assessed before surgery. FUNDING: U.S. National Institute on Aging.