14-3-3 proteins are a conserved family of 7 isoforms with diverse cellular functions found predominantly intracellularly. The 14-3-3η isoform is expressed extracellularly in the joints of patients with rheumatoid arthritis (RA) and expression in both serum and joint fluid correlates strongly with expression of metalloproteinases. 14-3-3η activates proinflammatory signalling cascades and inflammatory mediators relevant to the pathogenesis of RA. A new ELISA based assay has diagnostic utility for RA with sensitivity of 63.6% and specificity of 92.6% using the optimal cut-off from ROC analysis of 0.19ng/ml. Adding 14-3-3η to anti-cyclic citrullinated peptide antibodies (ACPA) resulted in an identification rate of 72% compared to 59% for ACPA alone. Adding rheumatoid factor (RF) to ACPA increased diagnostic capture from 59% to 72% and this increased further to 78% when 14-3-3η was added. Positive 14-3-3η status is also significantly associated with radiographic progression in early RA at years 1, 3 and 5 indicating prognostic utility. Extracellular 14-3-3η elicits the production of autoantibodies to the native protein, which also possess diagnostic utility. These do not correlate with expression of the protein and have complementary diagnostic utility. The presence of either the protein or its autoantibodies is observed in 90% of patients with early RA. Together with RF and/or ACPA this may result in identification of 95% of patients with early RA.