Objective. Osteoarthritis (OA) is a chronic rheumatic disease characterised by progressive cartilage destruction mediated by cytokines and other molecules. Chondrocyte activity and metabolism have attracted interest as targets of drug intervention, and spa-therapy can influence the serum levels of several cytokines. We investigated the effects of spa-therapy on clinical and ultrasonographic (US) findings and serum levels of cartilage oligomeric matrix protein (COMP) and several cytokines, chemokines, and growth factors in a prospective cohort of patients with symptomatic knee OA. Methods. Patients (n=53) with primary symptomatic knee OA were treated for 12 consecutive days with locally applied mud-packs. Assessments were made at baseline, immediately after completion of the treatment cycle, and 6 and 12 months after completion of treatment. They included visual analogue scale (VAS) ratings of pain, the Lequesne algofunctional index for knee OA, and US with calculation of a semi-quantitative score that expressed the severity of the local inflammatory process. Serum levels of 27 cytokines (including interferon-gamma-inducible protein-10 [IP-10]), chemokines, and growth factors were measured with multiplex bead-based immunoassays, and COMP levels were determined by ELISA. Results. US scores, VAS pain ratings, and Lequesne indexes indicated significant improvement after spa-therapy and at the 6- and 12-month follow-ups. Serum IP-10 levels also dropped significantly (p=0.0035), and this reduction was positively correlated with improvement of the Lequesne index (p=0.031). Conclusions. In patients with knee OA, spa-therapy can modulate serum levels of pro inflammatory cytokines/chemokines and produce improvements in joint pain and function that persists for up to I year.