Introduction：Siltuximab is a monoclonal antibody approved by the US Food and Drug Administration for interleukin-6 (IL-6). Numerous preclinical and clinical studies have revealed the pathological role of the IL-6 pathway in inflammation, autoimmune diseases, and cancer. The drug was approved in 2014 for the treatment of multicentric Castleman’s disease (MCD) and currently has a wide range of applications in the treatment of hematologic diseases. However, no previous studies have evaluated the safety of this drug in the treatment of hematologic disorders, and therefore the present study primarily reassessed the hematologic safety of this drug. Method：PubMed, EMBASE, and ClinicalTrials.gov were searched per the Preferred Reporting Items for Systematic reviews and Meta-Analyses statements for safety assessment while real-world pharmacovigilance data were mined via OpenVigil. Result：In all, four RCTs with 589 pooled patients were included. The safety evaluation revealed that treatment with siltuximab was associated with a propensity for thrombocytopenia (odds ratio [OR]: 1.67; 95% confidence interval [CI]: 1.16-2.40; p < 0.01), while the incidences of anemia and neutropenia were not significant. Regarding the analysis of real-world pharmacovigilance databases, siltuximab use was associated with a significant proclivity for anemia, neutropenia, and thrombocytopenia. Conclusion： The findings indicate that siltuximab is associated with a relatively high risk of anemia, neutropenia, and thrombocytopenia. Both clinicians and patients should exercise caution regarding these potential adverse events and make wise decisions.