Background <p>Previous studies have investigated the potential role of immune factors in chondrosarcoma (CHS). However, the causal relationship is unknown.</p> Methods <p>A two-sample Mendelian randomization (MR) was used to explore potential correlations between 731 immunocyte phenotypes, 91 inflammatory proteins, and CHS. The data were derived from published summary statistics of genome-wide association studies. Inverse-variance weighted was employed as the primary method. Furthermore, a range of analytical methods, including MR-Egger, weighted mode, and weighted median was used to enhance the robustness of the results. A two-step MR was used to assess the mediating effects of inflammatory proteins. Subsequently, sensitivity and MR Steiger directionality tests were performed.</p> Results <p>MR analyses showed that 12 immunocyte phenotypes were positively correlated with CHS (<i>P</i> &lt; 0.05, OR &gt; 1), and 11 immunocyte phenotypes were negatively correlated with CHS (<i>P</i> &lt; 0.05, OR &lt; 1). Five inflammatory proteins were positively associated with CHS (<i>P</i> &lt; 0.05, OR &gt; 1). No heterogeneous or horizontal pleiotropy was found. The MR Steiger analysis found no statistically significant evidence of reverse causation. Mediation analysis did not identify any potential mediating effects.</p> Conclusion <p>Our study underscores the pivotal role of immune factors in CHS and offers insights that can inform future research.</p>