Myofascial Pain Dysfunction (MPD) is a common musculoskeletal pain disorder with a female prevalence that may reach up to 60%. The aim of this randomized clinical trial (RCT) is to compare the usage of Platelet-Rich Plasma (PRP) and Botulinum toxin-A (BTX-A) injection in management of MPD. Patients and methods: the study included 27 female patients suffering from MPD related to masseter and temporalis muscles. They were selected from outpatient clinics of College of Oral and Dental Surgery, Misr University for Science and Technology (MUST) and Oral and Maxillofacial unit, Memorial Souad Kafafi University Hospital, MUST. Patients were randomly divided into two groups, “Group I" included 13 patients while “Group II" included 14 patients. Five trigger points were localized (3 in masseter and 2 in temporalis muscles). “Group I" was injected with 0.5 ml of PRP in each TrP, while “Group II" was injected with 5 units of BTX-A in each TrP. Assessment based on: Visual Analogue Scale (VAS) for subjective pain, Maximal Interincisal Opening (MIO), and Pressure Pain Intensity (PPI). Assessment was performed preoperatively and at follow-up periods of 4, 12, and 24 weeks. Results: At all follow-up periods, VAS scores for group I were significantly higher than group II. MIO results for group II were significantly higher than group I. Lastly, at all follow-up periods, PPI scores were significantly higher in group I than group II. Conclusions: BTX-A injection results are superior to that of PRP injection and could be considered a better treatment for MPD.