Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we performed single-cell RNAseq (scRNAseq) of interstitial cells in murine HFpEF. Diastolic dysfunction and fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Comparison with scRNAseq datasets of murine heart failure with reduced ejection fraction (HFrEF) identified a specific HFpEF fibroblast disease signature, characterized by overexpression of basement membrane and metabolic genes. While myofibroblast activation is known to be crucial for cardiac fibrosis in HFrEF, we found this cell-state switch to be less important in HFpEF. Disease specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes and main markers confirmed at protein level in murine samples. Furthermore, flow cytometry of whole heart tissue demonstrated a shift towards pro-inflammatory Ly6C^high monocytes/ macrophages in HFpEF. Ligand-receptor network analysis predicted several cell-cell communication axes between macrophages and fibroblasts in HFpEF hearts. Taken together, our results provide a characterization of the interstitial cellular landscape of murine HFpEF, including specific characteristics and mechanisms of fibroblast activation.