Background: Chronic pain and functional impairment interfere with the quality of life of subjects suffering from temporomandibular joint (TMJ) disorders. Intra-articular (IA) hyaluronic acid (HA) injections have been shown to alleviate pain and improve mandibular mobility in patients with TMJ osteoarthritis (OA). Objectives: The primary aim of the study was to identify the prognostic factors of patient satisfaction for a single IA injection of a mannitol-modified crosslinked HA (HANOX-M-XL) in patients with TMJ-OA. The second goal was to obtain clinical data on effectiveness, safety and mandibular mobility throughout a six-month follow-up period. Patients and methods:This was an observational single-arm prospective trial with a six-month follow-up. Inclusion criteria: patients with TMJ-OA which is not relieved by analgesics and/or non-steroidal-anti-inflammatory drugs and/ or orthotics, with radiological evidence of TMJ-OA. All patients received a single IA injection of 1 ml HANOX-M-XL in the target TMJ. The primary endpoint was patient satisfaction on day 180. The main secondary outcome measures were pain variation on a 11-point numeric scale (0-11) between the date of injection and month six, the variation over time of the Maximum Inter-Incisal Opening Distance (MIIOD) and the patient's assessment of effectiveness. Predictive factors of success or failure were also studied. All adverse events were recorded. Results: 36 subjects (mean age 55.3 years, mean disease duration 98 months), covering a total of 52 injected TMJs, were included. Between baseline and endpoint, the average pain while chewing decreased dramatically from 6.9 ± 1.2 to 2.9 ± 1.3 (p < 0.0001) and the MIIOD increased from 29 ± 7 to 35 ± 5 mm (p < 0.01). On day 180, all patients were satisfied with the treatment, with 34 patients (94%) rating it as highly effective or effective. Tolerability was good in all but one patient. In the multivariate analysis, patient satisfaction on day 180 was highly correlated with the pain.