BACKGROUND: An epidural steroid injection (ESI) effectively relieves acute lumbar discogenic radicular pain. Corticosteroids, a key ESI component, reduce pain by curbing inflammation and blocking pain signal transmission via C-fibers. While prior research confirms the efficacy of 40 mg and 80 mg methylprednisolone, the effectiveness of lower doses remains uncertain. OBJECTIVES: This trial aimed to compare the pain-relieving effects of ESI using varying methylprednisolone doses (10 mg, 20 mg, and 40 mg). Additionally, it sought to examine changes in fasting plasma glucose (FPG), serum cortisol, and serum adrenocorticotropic hormone (ACTH) levels across these groups. STUDY DESIGN: A prospective observational study. SETTING: Department of Pain Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, People’s Republic of China. METHODS: Ninety-three patients underwent a single epidural injection of methylprednisolone at different doses: 10 mg (n = 28), 20 mg (n = 32), and 40 mg (n = 33). We evaluated their Numeric Rating Scale (NRS-11) score and Oswestry Disability Index (ODI) score at preinjection and 7 days postinjection. We also measured FPG, serum cortisol, and ACTH levels at baseline and one day postinjection. RESULTS: Significant differences were observed in the likelihood of achieving substantial pain relief among the 3 groups at 7 days postinjection. Specifically, 10 mg vs 20 mg had an odds ratio (OR) of 6.546 (95% CI, 1.161 - 26.513, P = 0.008), and 10 mg vs 40 mg had an OR of 7.753 (95% CI, 1.98 - 30.353, P = 0.003). However, there was no significant difference between 40 mg and 20 mg, with an OR of 0.844 (95% CI, 0.239 - 2.987, P = 0.793) in Model 3. Additionally, the baseline NRS-11 score significantly predicted substantial pain relief, with an OR of 0.47 (95% CI, 0.287 - 0.768, P = 0.003). Furthermore, at 7 days postinjection, the ODI score was significantly lower in the 20 mg group (P = 0.007) and the 40 mg group (P < 0.001) compared to the 10 mg group. Moreover, the difference in serum cortisol and FPG between the 40 mg and 10 mg groups was more pronounced (P < 0.01), while the difference in ACTH was similar among all 3 groups (P = 0.191). LIMITATIONS: Potential selection bias and a short follow-up period may have influenced our study, and certain imaging results were omitted from the regression models. CONCLUSIONS: The effectiveness of ESI in relieving pain was found to be similar for both 20 mg and 40 mg doses, but with fewer changes in FPG and serum cortisol levels for the former (which were not statistically significant). As a result, it may be clinically viable to use a 20 mg dose for achieving short-term pain relief. Moreover, the baseline NRS-11 scores were found to be a reliable predictor of pain relief efficacy, with milder baseline pain intensity being associated with better pain relief outcomes. KEY WORDS: Epidural steroids, epidural injection, herniated disc, methylprednisolone, dose, cortisol, glucose, adrenocorticotropic hormone