The prevalent symptoms of oral submucous fibrosis (OSMF) are a burning sensation and trismus. The aim of the present study was to compare the efficacy of placentrex, hyaluronidase and dexamethasone, and their combination in the treatment of OSMF. For this purpose, 160 patients with OSMF were divided into four groups (each with 40 patients at a 1:1:1:1 allocation ratio). The patients in group 1 (control) received only oral supplements, along with regular mouth-opening exercises; patients in group 2 received an injection of placental extract; patients in group 3 were injected with hyaluronidase and dexamethasone; and patients in group 4 received a combination of injections from groups 2 and 3. The injections were administered once weekly for 12 weeks and patients were followed-up for 12 months. The data of the patients (mouth opening ability and a burning sensation) were analyzed using ANOVA and the Kruskal-Wallis test. The maximum increase in mouth opening (7.30±0.80 mm) was noted in group 4, and the lease increase was observed in the control group (0.37±0.16 mm), from baseline levels to the end of the 12th week. The maximum relapse in mouth opening of 1.62±0.45 mm was noted in group 2, and a minimum relapse of 0.20±0.08 mm was noted in group 4. On the whole, the present study demonstrates that the intralesional injection of a combination of the three drugs (placentrex, hyaluronidase and dexamethasone) in addition to the use of oral supplements and mouth opening exercises has a high level of efficacy in improving trismus and burning sensation in patients with OSMF.