The runt-related transcription factor 3 (RUNX3) regulates the differentiation of monocytes and their response to inflammation. However, the transcriptomic context ofRUNX3expression in blood monocytes remains poorly understood. We aim to learn aboutRUNX3from its relationships within transcriptomes of bulk CD14+ cells in adults. This study used immunomagnetically sorted CD14+ cell gene expression microarray data from the Multi-Ethnic Study of Atherosclerosis (MESA, n = 1202, GSE56047) and the Correlated Expression and Disease Association Research (CEDAR, n = 281, E-MTAB-6667) cohorts. The data were preprocessed, subjected toRUNX3-focused correlation analyses and random forest modeling, followed by the gene ontology analysis. Immunity-focused differential ratio analysis with intermediary inference (DRAIMI) was used to integrate the data with protein–protein interaction network. Correlation analysis ofRUNX3expression revealed the strongest positive association forEVL(rmean= 0.75, pFDR-MESA= 5.37 × 10−140, pFDR-CEDAR= 5.52 × 10−80),ARHGAP17(rmean= 0.74, pFDR-MESA= 1.13 × 10−169, pFDR-CEDAR= 9.20 × 10−59),DNMT1(rmean= 0.74, pFDR-MESA= 1.10 × 10−169, pFDR-CEDAR= 1.67 × 10−58), andCLEC16A(rmean= 0.72, pFDR-MESA= 3.51 × 10−154, pFDR-CEDAR= 2.27 × 10−55), while the top negative correlates wereC2ORF76(rmean= −0.57, pFDR-MESA= 8.70 × 10−94, pFDR-CEDAR= 1.31 × 10−25) andTBC1D7(rmean= −0.55, pFDR-MESA= 1.36 × 10−69, pFDR-CEDAR= 7.81 × 10−30). TheRUNX3-associated transcriptome signature was involved in mRNA metabolism, signal transduction, and the organization of cytoskeleton, chromosomes, and chromatin, which may all accompany mitosis. Transcriptomic context ofRUNX3expression in monocytes hints at its relationship with cell growth, shape maintenance, and aspects of the immune response, including tyrosine kinases.