Objective: Interleukin-6 (IL-6) is a crucial cytokine for treating rheumatoid arthritis (RA). Prognostic nutritional index (PNI) is a nutritional indicator originally developed for predicting prognosis after cancer surgery. This potentially has an association with IL-6 activity. We retrospectively assessed the relationship between PNI and disease activity index regarding IL-6 using unicentral retrospective cohort data. Methods: RA outpatients were chosen after examining the relationship between IL-6 signatures and PNI. In RA patients, correlations between PNI and 28-joints disease activity score using C-reactive protein (DAS28) were evaluated with methotrexate (MTX) administered or not (Phase 1), biologic or synthetic-targeted disease-modifying anti-rheumatic drugs (b/tsDMARDs) administered (Phase 2 or later). Studies were performed at initiation (baseline; BL) and every three months after. Results: After confirming a substantial correlation with IL-6 signatures, PNI showed a significant correlation with DAS28. Especially in Phase 1, when MTX was prescribed, and in Phase 2, when an IL-6 inhibitor, Janus Kinase (JAK) inhibitor, and tumor necrotizing factor (TNF) inhibitor with MTX prescription was administered, PNI at BL showed a significant correlation with the movement of DAS28 after that in IL-6 inhibitor administrated patients. Conclusions: PNI is associated with IL-6 activity and can predict DAS28 response after MTX and IL-6 inhibitors.