Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neuroinflammatory disorder often leading to demyelination of the spinal cord. Progression to HAM/TSP is closely associated with the high proviral load and the presence of virally infected CD4+ T cells that release extracellular vesicles (EVs). Exosomes, an EV subtype released by many cell types, transport proteins and nucleic acids that regulate intercellular communication and have been implicated in the progression of cancer and neuroinflammatory diseases. Herein, we have studied the effect of exosomes from HTLV-1 infected cells on the Peripheral Blood Mononuclear Cells (PBMCs) of HAM/TSP patients by single-cell sequencing utilizing innovative Honeycomb technology. We observed a distinct transcriptional response in monocyte populations compared with other immune cell types. Given that monocytes remain understudied in HTLV-1 pathogenesis, these findings highlight a potential role for infection-derived exosomes in shaping monocyte-driven immune dysregulation in HAM/TSP. A total of 41 genes were identified to be differentially expressed in HAM/TSP monocytes treated with exosomes; 28 were upregulated and 13 were downregulated. The most significantly altered genes are involved in chemokine activity and signaling, macrophage differentiation, lipid metabolism, and lysosomal function. Overall, our data suggests that exosome-treated HAM/TSP monocytes undergo immune remodeling that favors cell recruitment, activation, and a shift toward a mixed M1/M2-like phenotype. Such a shift may support viral persistence and chronic inflammation. These findings highlight a potential therapeutic pathway for addressing HTLV-1-induced neuroinflammation by modulating exosome-mediated signaling.