SUMMARY 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.