Background: Fibromyalgia is the second most common disease encountered in rheumatology practice Aim: This study designed to assess the potential effect of mesotherapy in treatment of tender points in primary fibromyalgia (PFM) patients. Methods: Thirty PFM patients who fulfilled the American Colleague of Rheumatology 1990 criteria, joined this study. They were divided into 2 groups randomly according to the treatment program received; Injection mesotherapy group (Group I: No=15 patients) who received a mixture of 2 ml of Ketoprofen (100mg/2ml) added to 3 ml of Saline Solution,  once cession per week for a total of 6 successive weeks and other 15 patients (Group II) who received Ketoprofen 100 mg Extended- Release capsules once daily for 2 successive weeks which represent the control group. Patients‟ pain severity, quality of life and depression were assessed  using visual analogue scale (VAS), fibromyalgia impact questionnaire (FIQ)  and the Hamilton Rating Scale (HDRS) respectively before treatment and after the 3rd & the 6th cession then data were recorded and compared. Results: We found significant improvements (p<0.001) tender point‟s number, VAS, FIQ and HDRS in the injection mesotherapy group compared to the control group with no major adverse effects were described. Conclusion: This study supports the hypothesis  that injection mesotherapy could offer a great therapeutic advantage in treatment of fibromyalgia tender points especially in the presence of associated comorbidities where there is a high risk of drug interaction, polypharmacy, or when conventional (oral or parenteral) NSAIDs use is contraindicated.