Chronic pain is frequently experienced by patients with heart failure (HF) and is associated with higher mortality, higher symptom burden, and worsened health-related quality of life. However, the genomic mechanisms underlying chronic pain in HF are understudied. Building an understanding of the mechanistic underpinnings of pain may inform novel interventions. The objective was to identify genes associated with pain from messenger RNA sequence data collected from patients with HF with and without pain. The current study analyzed data from 40 patients with HF previously enrolled in a clinical trial. Pain presence was measured using the Health Utilities Index Mark-3. Genes were tested for differential expression using DESeq2, and differentially expressed genes were analyzed for protein-protein interaction (PPI) and relevant ontological pathways using Metascape. Genes located within the core of the PPI network were considered key in disease-relevant biological pathways. Differentially expressed genes within this PPI network were reviewed in existing literature to narrow down candidate genes of interest. These target genes of interest were reanalyzed in a second sample of 24 patients with HF using validation quantitative polymerase chain reaction. A total of 334 genes (279 upregulated, 55 downregulated) were differentially expressed between patients with and without pain in the primary sample of 40. These genes were largely aligned with neutrophil degranulation pathways. Seven genes of interest were identified from a core network of 15 co-expressed genes in the PPI network and existing literature. Three of these seven genes, matrix metallopeptidase 8 ( MMP8 ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), and neutrophil defensin 3 ( DEFA3 ), were upregulated in patients with pain versus without pain in both the primary and validation samples. All seven genes of interest are involved in immune, inflammatory, and atherosclerotic processes. These results identify potential genes that may play a mechanistic role in chronic pain in HF. Further research is needed to evaluate these potential genes among clearly delineated pain phenotypes.