Purpose: The aim of this study was to assess the clinical effect of a single intra-articular injection of dexamethasone 21-palmitate (Lipotalon®) versus methylprednisolone acetate (Depomedrole) on the outcome of temporomandibular joint arthrocentesis. Patients and Methods: Eighteen females out of 38 patients (47.4%) did not respond to the used conservative therapy. Their ages ranged from 17-34 years, with an average of 24.2 years. . The patients were randomly assigned in into 1 of 2 equal groups. This group assignment was kept blinded to the patients and research candidate. Group A: Arthrocentesis with intra articular injection of ½ ml of lipotalon (4mg/ml) at the end of the procedure was performed.Group B: Arthrocentesis with intra articular injection of ½ml of Depomedrole (40mg/2ml) at the end of the procedure was performed. The clinical outcome measure parameters were assessed at baseline, i.e. before arthrocentesis, and then again at 1, 3 and 7 weeks and 5 months postoperatively. The evaluated parameters include assessment of articular pain (0 – 10 NRS), MMO and mandibular dysfunction as expressed by Helkimo index scores. Results: Both groups showed significant decrease in mean NRS, significant increase in the mean MMO and significant decrease in Helkimo index scores through all the study periods.The evaluated parameters showed insignificant difference between groups throughout the study intervals with the exception that the Lipotalon group showed statistically significant pain reduction 7 weeks postoperatively and statistically significantly higher mean increase’s percentage in MMO one week postoperatively than those of Depomedrole group. Conclusion: The efficacy of TMJ arthrocentesis with intra-articular injection of Lipotalon or Depomedrole was proved to reduce symptoms of pain and limited mouth opening and to maintain improvements over time.Comparison between the two groups revealed some superiority to the Lipotalon group over the Depomedrole group.