Objective <p>Some studies have shown an association between exposure to clonal hematopoiesis and autoimmune diseases, but whether there is a causal relationship still needs to be investigated.</p> Methods <p>To address this, our study initiated with rigorous quality control measures to identify and select single nucleotide polymorphisms strongly correlated with the exposure. Subsequently, we employed a multifaceted analytical approach, encompassing Inverse Variance Weighted, MR Egger, Weighted Median, Weighted Mode and Simple Mode. Our primary findings were grounded in the Inverse Variance Weighted model with random effects, complemented by sensitivity analyses. Heterogeneity was assessed using both Inverse Variance Weighted and MR-Egger, while pleiotropy was evaluated through MR-PRESSO. Additionally, a Leave-one-out analysis was conducted to pinpoint potentially influential SNPs.</p> Results <p>Our results revealed a statistically significant association between the small clone hematopoiesis and autoimmune disease (P &lt; 0.05). Notably, subsequent Inverse Variance Weighted and MR-Egger analyses failed to detect any inhibitory effect (P &gt; 0.05), suggesting no evidence of confounding. Furthermore, MR-PRESSO analysis confirmed the absence of horizontal pleiotropy (P &gt; 0.05). Conversely, the remaining groups did not yield significant findings.</p> Conclusions <p>This study presents compelling evidence for a causal relationship between clonal hematopoiesis and autoimmune diseases, offering novel insights into their genetic underpinnings.</p>