The objective of this study was to determine the diagnostic and prognostic values of antiglucose-6-phosphate isomerase (GPI) antibodies in patients with very early arthritis. Anti-GPI antibodies were measured by ELISA using purified GPI from rabbit muscle in: (i) 383 sera from healthy blood donors (n = 120), well-established rheumatoid arthritis (RA) (n = 99) and non-RA differentiated arthritis (NRADA) (n = 164) patients; (ii) 195 sera obtained from community-recruited patients with very early inflammatory arthritis (VErA cohort) that were studied for 1 year and classified as having RA (n = 116), NRADA (n = 41), and undifferentiated arthritis (UA) (n = 38) after the follow-up period. The criterion for severity was the progression of radiographic damage. Prevalence of anti-GPI antibodies was significantly higher in well-established RA patients (45·4%) compared to healthy subjects (2·5%). Anti-GPI antibodies were also present in sera from NRADA: systemic lupus erythematosus 53%, polymyositis 45·4%, adult-onset Still's disease 44%, systemic sclerosis 42·8%, spondylarthropathies 25% and primary Sjögren’s syndrome 5·8%. No significant association was found between the presence of anti-GPI antibodies and the 3 diagnostic groups from the VErA cohort. No correlation was observed between anti-GPI and autoantibodies usually associated with RA. Anti-GPI antibodies were not predictive of radiological progression in patients with very early arthritis. Thus, anti-GPI antibodies are not useful for discriminating RA from non-RA rheumatic diseases and do not constitute a predictive factor of structural damage.