Mud pack therapy is an alternative mode of treatment for rheumatic diseases. It is based on the application of heated mud packs to the entire body or to specific areas, such as over joints. The aim of the current study was to evaluate the efficacy of treatment with mud compresses at patients' homes for osteoarthritis of the knee. Fifty-eight patients with osteoarthritis of the knee were enrolled in a prospective, double-blinded, controlled study. Forty patients were treated with natural mineral-rich mud compresses and 18 patients were treated with mineral-depleted mud compresses. Mud compresses were applied 5 times each week during 3 weeks for a total of 15 treatments. Patients were assessed at baseline, at completion of the 3-week treatment period, and twice after the conclusion of the treatment period-after 1 month and after 3 months. The main outcome measures were the Lequesne Index of severity of knee osteoarthritis, patient self-assessment of pain, and severity of knee pain on a visual analog scale. A reduction of 20% or more in the pain scores was considered clinically significant. In the group treated with natural mud compresses, a significant reduction in knee pain was observed at all assessments. Similarly, improvement in the Lequesne Index was seen at the end of therapy and a month after treatment. In the control group, given mineral-depleted mud compresses, no significant change in knee pain was seen at any assessment. Improvement in the Lequesne Index was seen 1 and 3 months after completion of the therapy, but not at the end of therapy. Seventy-two percent of the patients in the treatment group had an improvement of >20% in self-assessment of knee pain, compared with 33% in the control group (p = 0.005). The data suggest that treatment with mud compresses, but only in their natural form, temporarily relieves pain in patients with osteoarthritis of the knees. We believe that treatment with mud compresses might augment conventional medical therapy in these patients.