Background: Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid‐lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta‐analysis of RCTs on the efficacy and safety of volanesorsen as compared to placebo treatment in patients with severe HTG. Methods: Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022. Results: Four studies showed significant reduction in TG after 3 months of treatment with volanesorsen as compared with placebo (MD: −73.9%; 95%CI: −93.5%, −54.2; p <.001 I2 = 89.05%; p <.001); VLDL‐C level (MD: −71.0%; 95%CI: −76.6%, −65.4%; p <.001 I2 = 94.1%; p <.001); Apo‐B48 level (MD: −69.03%; 95%CI: −98.59.4%, −39.47%; p <.001, I2 = 93.51%; p <.001) and Apo‐CIII level (MD: −80.0%; 95%CI: −97.5%, −62.5; p <.001 I2 = 94.1%; p <.001) with an increase in HDL‐C level (MD: +45.92%, 95%CI: +37.24%, +54.60%; p <.001 I2 = 94.34%; p <.001) and in LDL‐C level (MD: +68.6%, 95%CI: +7.0%, +130.1%; p <.001 I2 = 96.18%; p <.001) without a significant elevation of Apo‐B100 level (MD: +4.58%, 95%CI: −5.64%, +14.79%; p =.380 I2 = 95.09%; p <.001) in 139 volanesorsen patients as compared to 100 placebo‐treated controls. Most of adverse events were mild and related to local injection site reactions. Conclusions: In patients with severe HTG, volanesorsen is associated with a significant reduction in TG, VLDL‐C, Apo‐B48 and non‐HDL‐C and increment of HDL‐C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile. [ABSTRACT FROM AUTHOR]