Serum levels of hyaluronic acid (HA) and the amino-terminal type III procollagen peptide (NP-III-P) were determined simultaneously by specific immunoassays in patients with rheumatoid arthritis (n = 41), osteoarthritis (n = 43), ankylosing spondylitis (n = 7), psoriatic arthritis (n = 6), and reactive arthritis (n = 6). Increased serum levels of both HA and NP-III-P, were found in rheumatoid arthritis and - although less pronounced - in osteoarthritis, differing significantly from age- and sex-matched controls (n = 77). Furthermore, patients suffering from active rheumatoid arthritis showed higher serum levels of both antigens than patients with inactive disease, and significant correlations were found in rheumatoid arthritis between acute phase plasma proteins, HA and NP-III-P, respectively. In contrast, determination of low molecular weight fractions of NP-III-P by Fab- assay proved not to be useful in regard to clinical application. No significant effects of anti-inflammatory treatment were evident in any of the parameters. In rheumatoid patients, the serum concentrations of HA were found to correlate positively with the serum reactivity of NP-III-P related antigens (r = 0.692) and with the excretion of urinary pyridinoline (r = 0.455). Thus, both parameters seem to reflect similar mechanisms of connective tissue activation and may be related to inflammatory activity in joint diseases.