Psychosomatic syndromes have emerged as an important source of comorbidity in cardiac patients and have been associated with increased risk for adverse outcomes in patients with heart failure (HF). Understanding of the mechanisms underlying this connection is limited, however immune activity represents a possible pathway. While there have been numerous studies connecting immune activity to psychosomatic psychopathology, there is a lack of research on patients with HF. We examined forty-one consecutive outpatients affected by HF. We assessed psychosomatic psychopathology using the Diagnostic Criteria for Psychosomatic Research (DCPR) and the Patient Health Questionnaire-15 (PHQ-15). The Psychosocial Index (PSI) was used for assessing stress and psychosocial dimensions. Depression was evaluated with Beck Depression Inventory-II (BDI-II). Circulating levels of proinflammatory cytokines IL-6 and TNF-alpha were ascertained. Univariate and multivariable regression models were used to test for associations between inflammatory cytokines and psychosomatic psychopathology (i.e., DCPR syndromes, PHQ-15) and psychological dimensions (i.e., BDI-II, PSI). A significant positive correlation was found between IL-6 levels and psychosomatic psychopathology even when controlling for any confounding variables (i.e., Body-mass index (BMI), New York Heart Association (NYHA) class, smoking habits, alcohol consumption, statin use, aspirin use, beta blockers use, age, and gender). In contrast, the associations between TNF-alpha levels were non-significant. These findings can contribute to research in support of a psychoneuroimmune connection between psychosomatic psychopathology and HF. Findings also suggest the possibility that elevated IL-6 levels are more relevant for the pathogenesis of psychosomatic syndromes than for depression in patients with HF.