There is abundant evidence on inflammatory mechanisms in heart failure (HF) that are used for prognostication of the disease; however, data are lacking regarding the association between elevated cytokines, C-reactive protein (CRP), and cognition in HF. A cross-sectional pilot study of 38 patients with HF, aged 62 years (standard deviation± 9 years), predominantly men (68%) and Caucasian (79%) were screened for cognitive function using the Montreal Cognitive Assessment (MoCA). The study aimed to examine cognitive scores on MoCA with cytokines, interleukin 6 [IL-6] and tumor necrosis factor α [TNF-α], and CRP as indicators of early cognitive changes in HF. The result showed no direct correlation between cardiac variables and the MoCA score. The MoCA score, however, was inversely associated with IL-6 (r=-0.53, P=.001) and CRP (r=-0.34, P=.04), with no association to TNF-α. Regression analysis on the MoCA score and log-transformed IL-6 accounted for an additional 11% variation and remained statistically significant (P=.008) after controlling for covariates of education, living arrangements, and loneliness. The large effect size (R(2) =0.87) found in this pilot study provides rationale for a larger exploratory study to examine associations between cognitive function, cytokines, and CRP levels and help design future intervention studies.