Background: Chronic low back pain is a common painful medical problem which has significant socioeconomic impact. Conventional pharmacological therapy usually associated with adverse effects. Mesotherapy is the injection of active substances into the surface layer of the skin. This method allows a slower spread, higher levels, and longer lasting effects of drugs in the tissues underlying the site of injection compared with those following intramuscular injection. This technique is useful when a local pharmacological effect is required and relatively high doses of drug in the systemic circulation are not. Objective: The aim of this study was to compare mesotherapy versus conventional systemic administration of NSAIDs in chronic low back pain with sciatica (radicular pain). Patients and Methods: Fifty patients were randomized to receive anti-inflammatory therapy according to the following protocols: group I had received ketoprofen 100 mg (2 ml) + 2% lidocaine (1 ml) + saline (2 ml) for 4 injections. Group II had received: 100 mg ketoprofen orally twice daily. Results: After receiving treatment (After one and three months; As regarding VAS, repeated measure of the mean VAS score for each group separately showed statistically significant reduction (P < 0.01), and statistically highly significant higher percentage regarding sever grade of disability in group II (57.1% and 72.7%; respectively) compared with group I (42.9% and 27.3%; respectively) (P < 0.05). Conclusion: It could be concluded that the administration of NSAIDs via mesotherapy technique provides better therapeutic benefit than that induced by oral drug administration. That beside the lower drug amounts administered to patients undergoing mesotherapy and the low frequency of administration.