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Objectives Antiphospholipid syndrome(APS) is an autoimmune disease affecting approximately 2 people per 100,000 and the leading cause of strokes in people younger than 50 years of age. It is characterised by production of autoantibodies driving thrombotic outcomes. It can coexist with other autoimmune diseases, most commonly Systemic Lupus Erythematosus(SLE). Monocyte dysfunction in APS and SLE has been highlighted in several studies identifying monocytes as a site of synthesis for complement factors linking monocytes to APS disease manifestations. Our aim is to characterize the transcriptomic profile of specifically classical monocytes in APS, APS/SLE and SLE to identify potential subset differences between the conditions.Methods Classical monocytes(CD14+CD16-) from 8 APS, 8 APS/SLE, 8 SLE and 8 gender and age matched healthy controls (HCs) were sorted from peripheral blood mononuclear cells(PBMCs) using the BDS8 FACSDiscover. RNA was extracted and sequenced. Differentially expressed genes(DEGs) were determined by DESeq2 for 3 different comparisons: APS vs HC, APS/SLE vs HC and SLE vs HC. Pathway analysis was performed using Metascape.Results 1719 DEGs were identified in classical monocytes in APS vs HC, with 838 upregulated and 881 downregulated. Upregulated genes in APS were enriched in pathways involving response to molecules of bacterial origin, cellular response to cytokine stimulus and regulation of cell activation among others. Interestingly, complement genes(C2, CR3AR1 and CR5AR1) were within the top 20 differentially expressed genes in APS compared to HCs. Downregulated pathways in APS were predominantly related to RNA splicing. Only 393 DEGS were determined in APS/SLE vs HCs where 177 were upregulated and 216 downregulated. Unsurprisingly, cellular response to cytokine stimulus was one of the most enriched pathways. Downregulated pathways were linked to RNA splicing and mitochondrial metabolism. 1174 DEGs(580 upregulated and 594 downregulated) were found in SLE vs HC comparison including upregulation of cell activation, apoptotic signalling and downregulation of RNA/DNA metabolic processes as well as response to virus.Conclusions This is the first study showing Complement 2, complement C3a receptor 1(CR3AR1) and complement C5a receptor 1(CR5AR1) were among the most upregulated genes in classical monocytes in APS highlighting the differential role for complement in APS.