Objectives: Researchers have proposed biological (inflammation) and psychological (depression) factors as potential mechanisms for poorer outcomes and readmissions in heart failure (HF) patients. However, studies investigating the link between inflammation and depressive symptoms in these patients are few. We examined the relationships between levels of the inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and soluble tumor necrosis factor receptor 2 (sTNR2) and depressive symptoms in HF outpatients. Method: 55 patients (74.5% men; 60% Whites; mean age 71.6 ± 11.3 years) with New York Heart Association Class II, III, or IV HF (49%, 47%, and 4%, respectively) and mean ejection fraction (EF) 29.9 ± 7.1% completed the Patient Health Questionnaire (PHQ)-9 as a measure of depressive symptoms. We also obtained height, weight, and CRP, IL-6, and sTNFR2 levels. We used multivariate regressions to assess the predictive value of PHQ-9 scores on each inflammatory marker. Results: 22 (40%) participants reported depressive symptoms (PHQ-9 score ≥ 5). After controlling for age, gender, body mass index, HF etiology, EF, and statin use, we found significant relationships between levels of bothsTNFR2 (β =.35, p =.01) and IL-6 (β =.30, p =.04), but not CRP (β=_.96, p =.52), and depression scores. Conclusion: Our findings add to a growing body of evidence supporting the proposition that heightened inflammation explains the effect depression has on HF. Health care providers should screen for depression in HF patients, as they may be at higher risk of augmented inflammation and poor outcomes. © The Author(s) 2013.