BACKGROUND: Inflammatory conditions such as obesity and diabetes are linked to intermediate/non-classical monocyte activation, contributing to left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF). OBJECTIVE: To investigate whether circulating monocyte subtypes and their activity are associated with the presence LVDD and HFpEF. METHODS: We analyzed peripheral blood mononuclear cells (PBMCs) from 73 patients with or without LVDD/HFpEF. Cytokine secretion was measured post-stimulation, and gene expression was assessed via RNA sequencing. Monocyte subtypes were characterized using flow cytometry, and macrophage polarization was evaluated. We also examined the relationship between immunological markers and echocardiographic indicators of LVDD. RESULTS: Among the participants, 24 were controls, 23 had LVDD, and 26 had HFpEF. PBMCs from LVDD patients secreted significantly less Interleukin-6 compared to controls (2053 ± 708 pg/mL vs 12,273 ± 3357 pg/mL, p = 0.008). RNA sequencing indicated increased estrogen receptor pathway activity in LVDD. HFpEF patients exhibited a 1.5-fold increase in intermediate monocytes and a significant rise in non-classical monocytes compared to controls. Stimulated macrophages from LVDD and HFpEF patients showed less CD206/CD80 expression, indicating a shift towards M2-macrophage polarization. Notably, higher non-classical monocyte counts correlated with lower E' septal velocity, suggesting an association with diastolic impairment (β = -0.15, p = 0.041). CONCLUSIONS: LVDD and HFpEF are associated with a shift towards non-classical monocyte subtypes and higher numbers of non-classical monocytes are associated with signs of diastolic impairment. These findings highlight the importance of the inflammatory component in LVDD and HFpEF.