Abstract Objective Although anti-inflammatory drugs are commonly used in acute discogenic sciatica, data regarding their efficacy are scarce and controversial. We compared the efficacy and safety of intravenous ketoprofen and methylprednisolone with placebo in sciatica. Design Multicenter, double-blinded randomized controlled trial. Subjects Patients with confirmed discogenic acute sciatica, without neurologic deficit, were randomized into three arms. Methods Besides standard-of-care analgesic therapy, they received intravenous injections of methylprednisolone (60 mg/d) or ketoprofen (200 mg/d) or placebo for five days. The primary outcome was leg pain over five days. Secondary outcomes were clinical responses at days 3 and 5, lumbar pain, Straight Leg Raise Test and lumbar flexion index, analgesic consumption, realization of lumbar spine injections, and surgery during the study period. Results Fifty-four patients were randomized, and 50 completed the study. In patients admitted to the hospital for pain control with acute lumbar radicular pain due to intervertebral disc herniation and receiving an oral analgesic protocol including paracetamol, nefopam, tramadol, and morphine, there was no additional analgesic effect seen between groups. There was no significant difference in leg pain between the three groups over the study period. In the methylprednisolone group, however, we observed a higher rate of clinically relevant responses at day 3. No difference was observed on other secondary efficacy outcomes and safety. Conclusion No significant difference in leg pain was observed between groups. However, there was a higher proportion of patients relieved with intravenous methylprednisolone at day 3, compared with ketoprofen or placebo.