<p>The regulation of the immune system is crucial in the pathogenesis of various diseases. The direct involvement of immune cells in the development of rheumatoid arthritis (RA) and the potential mediation by metabolites remains to be elucidated. This study utilized a two-step, two-sample Mendelian randomization (MR) approach employing the inverse variance weighted (IVW) method to investigate the causal role of immune cells in RA and to assess the mediation effect of metabolites on the association between immune cells and RA. MR analyses identified 44 immune cell traits that were suggestively associated with RA. Additionally, five metabolites demonstrated protective effects against RA. Notably, mediation MR indicated that the causal role of CD14⁺ CD16⁻ monocyte activation complex (AC) on RA (total effect IVW: OR = 0.978, 95% CI [0.959, 0.998], <i>P</i> = 0.028) was significantly mediated by X-26109 levels, accounting for 7.32% of the total effect. This study provides evidence of a causal relationship between immune cells and RA, with metabolites potentially mediating this relationship.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> <p><b>Key Points</b></p> <p><i>• Mendelian randomization (MR) analysis was used to investigate the causal impact of immune cells on RA progression and the potential mediating role of metabolites, identifying 44 immune cell traits and several metabolites associated with RA risk</i></p> <p><i>• The study found that CD14</i> + <i>CD16 − monocyte activation complex (AC) is associated with a reduced RA risk, with this effect largely mediated by metabolite X-26109 levels, suggesting a potential therapeutic target for RA prevention and treatment</i></p> </entry> </row> </tbody> </tgroup> </Table></p>