Systemic sclerosis (SSc) is a rare autoimmune disorder with unmet medical needs. Prospective clinical studies have identified a pre-clinical stage, Pre-SSc (EULAR/ACR score <9), where individuals presenting with Raynaud's phenomenon and SSc-specific autoantibodies (autoAb), either anti-centromere B (CENP-B) or anti-topoisomerase I (Scl70), are at a high risk for progression within 5 years to limited (lcSSc) or diffuse (dcSSc) cutaneous SSc, respectively. Individuals with primary Raynaud's phenomenon (PR) and no autoAb are not at risk to develop SSc. Mononuclear phagocytes (MNPs) which include monocyte-derived cells, dendritic cells (DCs) and macrophages are a highly plastic group of cells implicated in both the inflammatory and end stage fibrotic processes in SSc. However, whether Pre-SSc  display a dysregulated systemic and skin inflammatory profile, and differences exist in the MNP landscape within Pre-SSc across autoAb subtypes, and versus PR, have not been explored. CITE-seq which simultaneously measured protein expression and transcriptome in matched skin and blood was instrumental to separate DC3 subsets and monocytes. Four DC3 subsets collectively represented a key mega cluster among MNPs in skin and blood. In Pre-SSc Scl70, some circulating and skin DC3 subsets were highly enriched for a type I interferon response signature relative to Pre-SSc CENP-B and PR. In contrast, Pre-SSc CENP-B DC3 subsets expressed a pro-inflammatory gene signature. In skin, a mature regulatory DC (mregDC) mega cluster, which includes two major subsets, was increased in Pre-SSc relative to PR, and expressed a distinct molecular profile across autoAb subtypes. Pro-inflammatory, mregDC, and type I interferon response signatures were modulated in lcSSc and dcSSc. Collectively, a dysregulated MNP landscape and differential targetable pathways in Pre-SSc represent a window of opportunity, at a pre-clinical stage, for therapeutic intervention to prevent disease progression.