OBJECTIVE Although a large number of independent studies have shown a paramount role for Proteus mirabilis in the aetiopathogenesis of rheumatoid arthritis (RA), this hypothesis is still controversial among rheumatologists. The main obstacle to its acceptance is the impression that increased Proteus antibodies in RA patients is a secondary phenomenon, occurring as the result of cross-reactivity between bacterial and self-antigens. To shed light on this problem, we examined the link between antibodies to various cross-reactive and non cross-reactive antigenic peptides from P. mirabilis and analysed the relationship between these antibodies and disease severity in patients with RA. METHODS Using the ELISA method, serum samples from 70 RA patients and 20 healthy controls were screened for total and class-specific antibodies against three human cross-reactive and non-crossreactive synthetic peptides from P. mirabilis haemolysin, urease C and urease F enzymes. An antibody index, which comprised the total concentration of antibodies against these peptides in each sample, was correlated with the biochemical parameters of disease activity and/or severity, such as the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and rheumatoid factors (RF). Furthermore, anti-peptide antibody indices were evaluated among RA patients with different levels of disease activity as defined by ESR and CRP. RESULTS Significantly elevated levels of total and class-specific IgG antibodies against the 3 Proteus peptides were observed among RA patients compared to healthy controls (p < 0.001). Active RA patients had elevated IgM antibodies against all peptides compared to healthy subjects (p < 0.001). However, no such elevation was observed in IgA anti-peptide antibodies in RA patients. A positive correlation was observed between the antibody indices and ESR (p < 0.001) and CRP (p < 0.01) concentrations, but not the RF status or disease duration. Furthermore, more than 90% of active RA patients showed positive values for the Proteus anti-peptide indices. CONCLUSIONS The elevated levels of antibodies against Proteus antigenic epitopes (which are cross-reactive or non cross-reactive with human tissue antigens) observed indicates that this enhanced bacterial immune response in RA patients is specifically triggered by Proteus microbes. Furthermore, the correlation of anti-peptide antibody indices with the biochemical markers of disease activity indicates that these antibodies exert damaging cytotoxic effects on joint tissues during the course of the disease.