The aim of this study was to assess serum levels and clinical significance of soluble CD26 (sCD26) and soluble CD30 (sCD30) in patients with rheumatoid arthritis (RA). Forty-eight patients with RA and 30 healthy controls were enrolled. Serum sCD26 and sCD30 levels were measured using ELISA. Serum sCD26 levels were significantly lower (P = 0.011), whereas sCD30 levels were higher (P = 0.008) in patients with RA than controls. Serum levels of sCD30 correlated significantly with clinical and laboratory parameters of disease activity like erythrocyte sedimentation rate, C-reactive protein, disease activity scores-28 and health assessment questionnaire score; however, sCD26 levels did not correlate any of these activity parameters. These results suggest that serum sCD30 levels increased and correlated significantly with disease activity, indicating a novel follow-up parameter in RA. Serum levels of sCD26 may be lessen but not related to disease activity in RA.