Spa therapy and short wave therapy are two of the most commonly used non-pharmacological approaches for osteoarthritis. The aim of this study was to assess their efficacy in comparison to conventional therapy in patients with osteoarthritis of the knee in a single blind, randomized, controlled trial. Seventy-four outpatients were enrolled; 30 patients were treated with a combination of daily local mud packs and arsenical ferruginous mineral bath water from the thermal resort of Levico Terme (Trento, Italy) for 3 weeks; 24 patients were treated with short wave therapy for the same period and 20 patients continued regular, routine ambulatory care. Patients were assessed at baseline, upon completion of the 3-week treatment period, and 12 weeks later. Spa therapy and short wave therapy both demonstrated effective symptomatic treatment in osteoarthritis of the knee at the end of the treatment, but only the spa therapy was shown to have efficacy persistent over time. Our study demonstrated the superiority of arsenical ferruginous spa therapy compared to short wave therapy in the treatment of osteoarthritis of the knee, probably in relationship to the specific effects of the minerals in this water.