In a single-blind, randomized clinical trial, both the efficacy and safety of hyaluronic acid (HA) were compared with that of mucopolysaccharide polysulfuric acid ester (MPA) in patients with osteoarthritis of the knee joint. Both agents were administered intra-articularly over six weeks. Patients received either seven injections of HA or 13 injections of MPA. Joint function, range of motion, severity of pain, the general condition of the bony structure and soft tissue of the joint area, and the global clinical efficacy and safety of the medication were assessed. The mean improvement in the modified total Larson rating score was 22% (SD = 28) after HA treatment and 7% (SD = 17) after treatment with MPA (analysis of variance: p = 0.02). This change was mainly caused by a reduction of pain. The onset of pain relief was more rapid in the HA group. The therapeutic effect increased in both treatment groups during the follow-up period. During this interval, lasting six months after the start of treatment, a further reduction of pain and an improvement of knee joint function could be observed. At the end of the study, 25 out of 33 (76%) patients in the HA group and 11 out of 24 (46%) patients in the MPA group were symptom-free or markedly improved (Chi-square test: p = 0.02). Both agents were tolerated very well.