Background Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease characterized by increased platelet destruction and impaired thrombopoiesis. Platelet indices changes depending on the morphology and volume of platelets. Serum lipids have been found to affect platelet formation and activity in certain diseases, thus induce the corresponding variation of platelet indices.Methods Mendelian randomization (MR) analysis was performed based on databases. The clinical data from 457 ITP patients were retrospectively collected and analyzed, including platelet indices, serum lipids, hemorrhage and therapeutic response.Results MR analysis showed low high-density-lipoprotein-cholesterol (HDL-C), low apolipoprotein A-1, high triglyceride (TG) and high apolipoprotein B (ApoB) causing high platelet distribution width (PDW); high low-density-lipoprotein-cholesterol (LDL-C) increasing mean platelet volume (MPV). In ITP, there were positive correlations between platelet count with TG, PDW with HDL-C and ApoB, and plateletcrit with TG and non-esterified fatty acid, and the correlation had gender differences. Bleeding scores were negatively corelated with cholesterol and LDL-C. LDL-C and homocysteine were risk factors for therapeutic response.Conclusions Serum lipids, especially cholesterol were tightly correlated with platelet indices, hemorrhage and therapeutic effects in ITP patients. These results provide clinical references for the management of serum lipids, and highlight the necessity to further explore the relationship between lipids and pathogenesis of ITP.Trial registration: No: NCT05095896, October 14, 2021, retrospectively registered.