BACKGROUND: Although the precise cause of the co-occurrence of pyoderma gangrenosum (PG) and inflammatory bowel disease (IBD) is still unknown, prior research has shown that the two conditions coexist. Moreover, it is currently unknown how immune cells function in influencing the relationship between IBD and PG. METHODS: In order to choose independent single nucleotide polymorphism (SNP) as instrumental variables, we were provided with genome-wide association study (GWAS) summary data of European populations from the IEU OpenGWAS project (for IBD) and a the FinnGen database (for PG) publically available. For the MR analysis, a range of analytical techniques were employed to peer into the possible causative relationship between PG and IBD. The two-step MR analysis was used to investigate the mediating role of immune cells between IBD and PG. The chief method utilized was the inverse variance weighted (IVW) approach. Using the Cochran's Q test and the MR-Egger intercept, respectively, heterogeneity or pleiotropy was evaluated to support the findings. MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) were used to identify the outlier SNP. RESULTS: IBD was found to raise the incidence of PG (IVW-FE: OR = 1.604, 95%CI = 1.308-1.966, p = 5.58 × 10), according to MR findings. Moreover, UC or CD were strongly correlated with a greater risk of PG (OR = 1.339, 95%CI = 1.041-1.723, p = 0.023 for UC; OR = 1.339, 95%CI = 1.107-1.621, p = 0.003 for CD). The results of the reverse MR study did not suggest a connection between PG and IBD. CD4 regulatory T cell is the mediator that particularly stood out in the interaction between UC and PG. There was evidence of neither heterogeneity nor horizontal pleiotropy. And the validity of these conclusions was verified. CONCLUSION: In the European population, PG risk may be genetically elevated by IBD, including CD and UC, according to the current study. The effect of UC on PG may have been causally mediated by CD4 regulatory T cells.