Despite advances in pharmacological therapy, physical treatment continues to be important in the management of ankylosing spondylitis (AS). The objective of the present study was to evaluate the effects and tolerability of combined spa therapy and rehabilitation in a group of AS patients being treated with TNF inhibitors. Thirty AS patients attending the Rheumatology Unit of the University of Padova being treated with TNF inhibitors for at least 3 months were randomized and assessed by an investigator independent from the spa staff: 15 were prescribed 10 sessions of spa therapy (mud packs and thermal baths) and rehabilitation (exercises in a thermal pool) and the other 15 were considered controls. The patients in both groups had been receiving anti-TNF agents for at least three months. The outcome measures utilized were BASFI, BASDAI, BASMI, VAS for back pain and HAQ. The evaluations were performed in all patients at the entry to the study, at the end of the spa treatment, and after 3 and 6 months. Most of the evaluation indices were significantly improved at the end of the spa treatment, as well as at the 3 and 6 months follow-up assessments. No significant alterations in the evaluation indices were found in the control group. Combined spa therapy and rehabilitation caused a clear, long-term clinical improvement in AS patients being treated with TNF inhibitors. Thermal treatment was found to be well tolerated and none of the patients had disease relapse.