Abstract The etiology of rheumatoid arthritis (RA) is unknown. Previous studies of mouse models of RA have strongly implicated the alternative and lectin pathways of the complement system in disease pathogenesis. Here we explored the Pathobiology of Early Arthritis Cohort (PEAC) tissue RNA sequencing (RNA-seq) database and identify correlations among complement gene expression, Fc receptor expression and clinical severity, measured as disease activity score 28 - erythrocyte sendimentation rate (DAS28-ESR), in both blood and synovium. We also evaluated the biodistribution of complement activation pathway proteins and inhibitors using Multispectral ImmunoHistoChemical (MIHC) staining. Ultrasound guided synovial biopsies (n = 23), obtained from Accelerating Medicines Partnership (AMP) studies, were subjected to MIHC for various complement proteins. Our analyses revealed that in the synovium, but not in blood, significant positive correlations existed between complement gene expression and DAS28-ESR for C2, CFB, FCN1, C3AR1, C5AR1, and CR1. Surprisingly, levels of MASP1, Colec12, C5 and C6 RNA inversely correlated with baseline DAS28-ESR. After 6 months therapy, baseline CFHR4 positively correlated with delta DAS28-ESR. In the synovium, there were also significant positive correlations between DAS28-ESR and FcγR1A, FcγR1B, FcγR2A and FcγR3A. In early RA (ERA) synovium, a significantly (p < 0.05) higher levels of cells expressed CFH compared with CFB and CFHR4. We also found regional imbalance between C3 and CFH in ERA synovial biopsies. ERA synovial biopsies implicate the complement system in early disease and reveal intriguing differences among factors in clinical relevance, outcome and localized tissue dysregulation. Supported by R01AR51749-16